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THE DISPENSATORY 

OF THE UNITED STATES 
OF AMERICA 25th Edition 



OSOL-FARRAR 



Synopsis of Arrangement 
United States Dispensatory 



PART ONE: Drugs recognized by The United States 
Pharmacopeia, British Pharmacopoeia, International 
Pharmacopoeia, or The National Formulary. 

Individual monographs are arranged alphabetically according to the Eng- 
lish title, with information for each drug in general following the order: 

• Official Tides and Synonyms 

• Official Definition 

• Unofficial Synonyms, Foreign Language Tides (official 

titles appear in bold-face type) , Trade-names and Trade- 
marks (name of manufacturer indicated parenthetically) 

• Source or Manufacturing Process; History 

• Official Description; Tests 

• Assay Methods 

• Constituents 

• Adulterants 

• Therapeutic Actions and Uses 

• Toxicology 

• Dosage 

• Storage Requirements 

• Official Preparations 

• Usual Sizes (for dosage forms) 

PART TWO: Drugs not official in The United States 

Pharmacopeia, British Pharmacopoeia, International 
Pharmacopoeia, or The National Formulary. 

Individual monographs are arranged alphabetically, with 
information for each drug following the order listed above. 

PART THREE : Veterinary Uses and Doses of Drugs 

COMPLETE INDEX 



Table of Metric Doses 
with Approximate Apothecary Equivalents 



The approximate dose equivalents in the following table represent the quantities usually prescribed, under 
identical conditions, by physicians trained, respectively, in the metric or in the apothecary system of weights 
and measures. In labeling dosage forms in both the metric and the apothecary systems, if one is the approxi- 
mate equivalent of the other, the approximate figure shall be enclosed in parentheses. 

When prepared dosage forms such as tablets, capsules, pills, etc., are prescribed in the metric system, the 
pharmacist may dispense the corresponding approximate equivalent in the apothecary system, and vice 
versa, as indicated in the following table. 

Caution — For the conversion of specific quantities in a prescription which requires compounding, or in 
converting a pharmaceutical formula from one system of weights or measures to the other, exact equivalents 
must be used. 



Liquid Measure 




Liquid Measure 




Approximate 






Approximate 




Apothecary 






Apothecary 


Metric 


Equivalents 


Metric 


Equivalents 


1000 ml. 


1 quart 


3 


ml. 


45 


minims 


750 ml. 


1 Vz pints 


2 


ml. 


30 


minims 


500 ml. 


1 pint 


1 


ml. 


15 


minims 


250 ml. 


8 fluidounces 


0.75 ml. 


12 


minims 


200 ml. 


7 fluidounces 


0.6 


ml. 


10 


minims 


100 ml. 


3V4 fluidounces 


0.5 


ml. 


8 


minims 


50 ml. 


1% fluidounces 


0.3 


ml. 


5 


minims 


30 ml. 


1 fluidounce 


0.25 ml. 


4 


minims 


15 ml. 


4 fluidrachms 


0.2 


ml. 


3 


minims 


10 ml. 


254 fluidrachms 


0.1 


ml. 


V/z 


minims 


8 ml. 


2 fluidrachms 


0.06 ml. 


1 


minim 


5 ml. 


1 54 fluidrachms 


0.05 ml. 


% 


minim 


4 ml. 


1 fluidrachm 


0.03 ml. 


Vz 


minim 




Weight 






Weight 






Approximate 






Approximate 




Apothecary 






Apothecary 


Metric 


Equivalents 


Metric 


Equivalents 


30 Gm. 


1 ounce 


30 


mg. 


y 2 


grain 


15 Gm. 


4 drachms 


25 


mg. 


% 


grain 


10 Gm. 


2/4 drachms 


20 


mg. 


Vz 


grain 


7.5 Gm. 


2 drachms 


15 


mg. 


V* 


grain 


6 Gm. 


90 grains 


12 


mg. 


% 


grain 


5 Gm. 


75 grains 


10 


mg. 


% 


grain 


4 Gm. 


60 grains (1 drachm) 


8 


mg. 


y* 


grain 


3 Gm. 


45 grains 


6 


mg. 


%0 


grain 


2 Gm. 


30 grains {Vz drachm) 


5 


mg. 


VVL 


grain 


1.5 Gm. 


22 grains 


4 


mg. 


%5 


grain 


1 Gm. 


15 grains 


3 


mg. 


Y20 


grain 


750 mg. 


12 grains 


2 


mg. 


%0 


grain 


600 mg. 


10 grains 


1.5 


mg. 


y 40 


grain 


500 mg. 


7/4 grains 


1.2 


mg. 


Vm 


grain 


400 mg. 


6 grains 


1 


mg. 


Yeo 


grain 


300 mg. 


5 grains 


800 


meg. 


Yso 


grain 


250 mg. 


4 grains 


600 


meg. 


Yioo 


grain 


200 mg. 


3 grains 


500 


meg. 


Yl20 


grain 


150 mg. 


254 grains 


400 


meg. 


M50 grain 


120 mg. 


2 grains 


300 


meg. 


Y200 


grain 


100 mg. 


1 Vz grains 


250 


meg. 


%50 


grain 


75 mg. 


1 54 grains 


200 


meg. 


%00 


grain 


60 mg. 


1 grain 


150 


meg. 


■54oo 


grain 


50 mg. 


% grain 


120 


meg. 


Yooo 


grain 


40 mg. 


Vi grain 


100 


meg. 


%00 


grain 



Note: A cubic centimeter (cc.) is the approximate equivalent of a milliliter (ml.). 

The above approximate dose equivalents have been adopted by the latest Pharmacopeia, National Formulary, and 
New and Non-official Remedies, and these dose equivalents have the approval of the Federal Food and Drug 
Administration. 



THE DISPENSATORY 

OF THE UNITED STATES 
OF AMERICA ** 





NOV 16198* 

THfc CORNER PHARMACY 

NOV 16 195f 




Contributors 



Howard N. Baier, b.s., m.d., m.s. 

Associate in Medicine and Physiology, Temple Uni- 
versity School of Medicine and Hospital. 

Mahlon Z. Bierly, Jr., b.s., m.d. 
Assistant Physician, Visiting Staff, Children's Hospi- 
tal of Philadelphia; Assistant Pediatrician to OPD, 
Bryn Mawr Hospital. 

Eleanor E. Buckley, b.s. 

Staff Writer, Medical Department Wyeth Laboratories, 
Inc. 

Peter T. Cassalia, b.s., d.d.s., m.s. 

Chief of Oral Surgery, Northeastern Hospital and 
Lower Bucks County Hospital. 

Dean A. Collins, a.b., a.m., ph.d., m.d. 

Professor and Head of the Department of Pharma- 
cology, Temple University School of Medicine. 

David W. Crjsman, b.s., v.m.d. 

Assistant Professor of Microbiology, School of Veteri- 
nary Medicine, University of Pennsylvania. 

Elmer H. Funk, Jr., b.s., m.d. 

Assistant in Aiedicine, Jefferson Medical College: 

Assistant Cardiologist to Out-Patients, Pennsylvania 

Hospital. 

Joan H. Long Gault, b.s., m.d., m.s. 

Instructor in Medicine, Temple University School of 
Medicine. 

Alfonso R. Gennaro, b.s., m.s. 

Instructor in Chemistry, Philadelphia College of Phar- 
macy and Science. 



Elizabeth W. Johnson, b.s., m.s. 

Librarian, Philadelphia College of Pharmacy 
Science. 

Lawrence R. Mallery, Jr. 

Medical Writer, Gray & Rogers, Philadelphia 



and 



John E. Martin, v.m.d. 

Assistant Professor of Physiology and Pharmacology, 
School of Veterinary Medicine and Graduate School of 
Medicine, University of Pennsylvania. 

Morton J. Oppenheimer, a.b., m.ed., m.d. 

Professor and Head of the Department of Physiology, 
Temple University School of Medicine and Hospital. 

Edward F. Roberts, a.b., ph.d., m.d. 

Director of Clinical Investigation, Wyeth Labora- 
tories, Inc. 

Bruce S. Roxby, b.s., m.d., m.s. 

Instructor in Medicine, Temple University School of 
Medicine and Hospital; Director of Health Service, 
Temple University. 

John B. Roxby, Jr., b.a., m.a., m.d. 

Associate in Dermatology, Temple University School 
of Medicine and Hospital; Dermatologist, Chestnut 
Hill Hospital and Northern Division, Philadelphia 
General Hospital. 

Joseph Seifter, a.b., ph.d., m.d. 

Director, Wyeth Institute for Medical Research; Lec- 
turer in Pharmacology, Graduate School of Medicine, 
University of Pennsylvania. 

Daniel L. Shaw, Jr., b.s., m.d. 

Director of Clinical Research, Wyeth Laboratories, 
Inc. ; Instructor in Medicine, Jefferson Medical College. 

Charles R. Shuman, b.a., m.d., m.s. 

Associate in Medicine, Temple University School of 
Medicine and Hospital; Consultant in Metabolic Dis- 
ease, Philadelphia Veterans Administration Hospital. 

Chris J. D. Zarafonetis, b.a., m.d., m.s. 

Associate Professor of Medicine, Temple University 
School of Medicine and Hospital ; Chief, Hematology 
Division, Temple University Hospital. 



THE DISPENSATORY 

OF THE UNITED STATES 
OF AMERICA *•> 25th Edition 

ARTHUR OSOL, Ph.G., B.S., M.S., Ph.D. 

PROFESSOR OF CHEMISTRY AND DIRECTOR OF THE DEPARTMENT AND SCHOOL OF CHEMISTRY, PHILADELPHIA COLLEGE 
OF PHARMACY AND SCIENCE; MEMBER OF THE COMMITTEE OF REVISION OF THE UNITED STATES PHARMACOPEIA 

GEORGE E. FARRAR, Jr., B.S., M.D., F.A.C.P. 

MEDICAL DIRECTOR, WYETH LABORATORIES, INC.; ASSOCIATE PROFESSOR OF MEDICINE, TEMPLE UNIVERSITY SCHOOL 
OF MEDICINE AND HOSPITAL; MEMBER OF THE COMMITTEE OF REVISION OF THE UNITED STATES PHARMACOPEIA 

WITH 
KARL H. BEYER, Jr., b.s., ph.d., m.d. DAVID K. DETWEILER, v.m.d., m.s. 

LECTURER IN PHARMACOLOGY, GRADUATE SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR OF VETERINARY PHARMACOLOGY, SCHOOL 

UNIVERSITY OF PENNSYLVANIA, AND TEMPLE UNIVERSITY OF VETERINARY MEDICINE, GRADUATE SCHOOL OF ARTS AND 

SCHOOL OF MEDICINE; ASSISTANT DIRECTOR OF RESEARCH, SCIENCES, AND THE GRADUATE SCHOOL OF MEDICINE, UNIVER- 
SHARP & DOHME DIVISION, MERCK St CO., INC. SITY OF PENNSYLVANIA 

JOHN H. BROWN, v.m.d. ROBERTSON PRATT, a.b., ph.d. 

PRODUCTION MANAGER, MARIETTA BIOLOGICAL LABORATORY, PROFESSOR OF PHARMACOGNOSY AND ANTIBIOTICS, UNIVERSITY 

WYETH LABORATORIES, INC. OF CALIFORNIA COLLEGE OF PHARMACY 

HEBER W. YOUNGKEN, ph.m., ph.d., sc.d. 

RESEARCH PROFESSOR OF PHARMACOGNOSY AND BOTANY, MASSA- 
CHUSETTS COLLEGE OF PHARMACY; MEMBER OF THE COMMITTEE 
OF REVISION OF THE UNITED STATES PHARMACOPEIA. 

Editor Emeritus 
HORATIO C. WOOD, Jr., M.D., Ph.M. 

PROFESSOR EMERITUS OF PHARMACOLOGY, PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE; 
EMERITUS PROFESSOR, GRADUATE SCHOOL OF MEDICINE, UNIVERSITY OF PENNSYLVANIA 



Based on the Fifteenth Revision of The United States Pharmacopeia, the Tenth 

Edition of The National Formulary, The British Pharmacopoeia, 1953, the First 

Edition of the International Pharmacopoeia, Volumes I and 11 




Philadelphia ^|[jigg|^ Montreal 

J. B. LIPPINCOTT COMPANY 



THE DISPENSATORY OF THE UNITED STATES OF AMERICA 

\th Edition 



25' 



Copyright 1955 by J. B. LIPPINCOTT COMPANY 
© 1955 by J. B. LIPPINCOTT COMPANY 



Entered, according to Act of Congress, in the year 1877, 

By George B. Wood, m.d., 
In the Office of the Librarian of Congress at Washington 



Copyright, 1888, 1894, 1899, 1907, by H. C. Wood, M.D. 



, Copyright, 1918, 1926, 1937, 1943, by H. C. Wood, Jr., m.d. 



Copyright, 1947, 1950, by J. B. LiPPiNCOTT Company 



The use in this volume of certain portions of the text of the United States Pharmacopeia, Fifteenth 
Revision, official December 15, 1955, is by virtue of permission received from the Board of Trustees of the 
United States Pharmacopceial Convention. The said Board of Trustees is not responsible for any inaccuracy 
of quotation nor for any errors in the statement of quantities or percentage strengths. 

Permission to use for comment parts of the text of the National Formulary, Tenth Edition, in this volume 
has been granted by the Committee on Publications by authority of the Council of the American Pharmaceutical 
Association. 



Distributed in Great Britain by 

Pitman Medical Publishing Co., Limited 

London 



Library of Congress 

Catalog Card Number 

7-31327 



Printed in the United States of America 



Historical Title Page 



Editors 

First Edition (1833) to Eleventh Edition (1858) 
GEORGE B. WOOD and FRANKLIN BACHE 



Twelfth Edition (1865) and Thirteenth Edition (1870) 
GEORGE B. WOOD 



Fourteenth Edition (1877) 
GEORGE B. WOOD and HORATIO C. WOOD 



Fifteenth Edition (1883) to Nineteenth Edition (1907) 
HORATIO C WOOD, JOSEPH P. REMINGTON and SAMUEL P. SADTLER 



Twentieth Edition (1918) 
JOSEPH P. REMINGTON and HORATIO C. WOOD, Jr. 



Twenty-first Edition (1926) and Twenty-second Edition (1937) 
HORATIO C WOOD, Jr., and CHARLES H. LaWALL 



Twenty-third Edition (1943) 
HORATIO C WOOD, Jr., and ARTHUR OSOL 



Twenty-fourth Edition (1947) 
ARTHUR OSOL and GEORGE E. FARRAR, Jr. 



The following have also been employed as Associate Editors in the preparation of the 
various editions: 



WILLIAM PROCTER 
ROBERT BRIDGES 
HENRY H. RUSBY 
HENRY KRAEMER 
ALBERT B. LYONS 
JOHN F. ANDERSON 



LOUIS GERSHENFELD 
HEBER W. YOUNGKEN 
IVOR GRIFFITH 
ARTHUR OSOL 
E. EMERSON LEUALLEN 
WILLARD F. VERWEY 



Publishers 



First to Eighth Edition 
GRIGG & ELLIOT 

Ninth to Eleventh Edition 
LIPPINCOTT, GRAMBO & CO. 



Twelfth to Fourteenth Edition 
J. B. LIPPINCOTT & CO. 

Fifteenth to Twenty-fourth Edition 
J. B. LIPPINCOTT COMPANY 



Preface 






This new edition of the UNITED STATES 
DISPENSATORY documents the progress of 
knowledge concerning medicinal agents in an era 
of unprecedented development and expansion in 
this field of medical service. In no period of the 
long history of this book has so much new infor- 
mation been incorporated and so extensive a re- 
vision of older information been consummated. 
This is in large measure attributable to the fact, 
on the one hand, that many medicinal substances 
have hardly reached therapeutic maturity before 
they are replaced by even safer and more effective 
drugs and, on the other, to the finding of new 
uses for older drugs as research has disclosed 
hitherto unrecognized therapeutic applications or 
led to the isolation, in the case of drugs of natural 
origin, of potent and therapeutically effective 
constituents. 

The total of new admissions to the United 
States Pharmacopeia, the National Formulary, the 
British Pharmacopoeia, and the two volumes of 
the International Pharmacopoeia, together with 
the new non-official drugs described for the first 
time in this edition of the DISPENSATORY, 
exceeds 500. 

While maintaining the traditional treatment of 
drugs according to alphabetic arrangement — which 
has many advantages — a feature of this edition 
of the DISPENSATORY is the inclusion of many 
new general survey articles on pharmacological 
classes of drugs. Thus, there appear in Part Two 
articles on the following: Adrenergic Blocking 
Agents, Anticoagulant Drugs, Antihistamines, Anti- 
metabolites, Barbiturates, Curarimimetic Agents 
and their Antagonists, Ganglionic Blocking Agents, 
Local Anesthetic Agents, Nephrotropic Agents, 
Parasympathetic Blocking Agents, Parasympa- 
thomimetic Agents and Cholinesterase Inhibitors, 
and Skeletal Antispasmodic Compounds. These 
articles provide the basis for comparing drugs in 
the several categories indicated; also, a correla- 
tion between pharmacological action and chemical 
structure is thereby often possible, especially since 
these general articles are amply illustrated with 
structural formulas. Certain other general articles 
have been completely rewritten as, for example, 
that on Antibiotics, also in Part Two. The estab- 
lished uses of radioisotopes in medicine have 
naturally necessitated addition of a general 
article on this subject, in addition to a specific 
article on the official Sodium Radio-iodide (I 131 ) 
Solution and innumerable references throughout 
the book to specific uses of radioisotopes as tracer 
substances. 



As in preceding editions of the DISPENSA- 
TORY, all articles are amply documented by 
original literature references in order to establish 
the authority for the information that is provided 
and to facilitate further search of the literature 
when this is required. In this connection it may 
be noted that the new information for this edi- 
tion was chosen from more than 25,000 issues of 
the approximately 400 medical, pharmaceutical, 
biological, and chemical journals which are regu- 
larly available to the editors as the basis for re- 
vision of the DISPENSATORY. 

The very thorough investigations now required 
for new drugs before they are released for clinical 
use, together with the more extensive clinical 
reporting of them, has inevitably resulted in 
lengthier monographs concerning individual drugs. 
Since oftimes our readers may wish to have only 
the most essential information concerning uses of 
a drug, we have provided for the lengthier articles 
a brief outline of uses at the beginning of the sec- 
tion thus designated. Where the articles are of 
necessity very long, a summary section has also 
been provided, this following the section on uses. 
Also, to facilitate quick location of specific in- 
formation about drugs having a variety of actions 
and uses, the monographs have been conspicuously 
and informatively captioned to indicate specific 
actions and uses. 

Dosage data have been considerably amplified 
in this edition. The range of dose, the maximum 
single dose, and the maximum total dose in 24 
hours are provided for most drugs; variations of 
dosage in different diseases are indicated where 
such information is required; comparison of dif- 
ferent routes of administration is also included 
where a choice is available. Toxicological data 
have also been expanded and methods of treat- 
ment of poisoning are described in sufficient detail 
to be of practical utility. 

The section on Veterinary Uses and Doses of 
Drugs, which was introduced in the 24th Edition 
of the Dispensatory and has found wide accept- 
ance, has been enlarged by 63 pages both by in- 
clusion of new drugs and new data for older ones. 

To provide space for the abundance of new 
material included, this edition contains over 200 
pages more than its predecessor; 102 pages more 
were made available by the deletion of general 
tests, processes and reagents formerly comprising 
Part Three of the DISPENSATORY which, while 
important, are of secondary importance to the 



viii PREFACE 

main purpose of this book in providing practical names are listed opposite the title page; it has 

and up-to-the-minute information about drugs. become increasingly apparent in this fruitful 

Further savings of space were made by deletion or period of medicinals development that the collabo- 

curtailment of information concerning drugs which ration of specialists is essential in order to provide 

are no longer or only very rarely used; the editors the thorough and authoritative treatment of the 

were not unmindful, however, of the expectation subject required in the DISPENSATORY. Finally, 

of users of the DISPENSATORY to find infor- the many contributions of Walter Kahoe, Ph.D., 

mation concerning unusual drugs. A new and Director of the Medical Department of J. B. 

somewhat more condensed typography in Part Lippincott Company, toward the culmination of 

Two permitted more information to be included the editorial effort in the production of the printed 

therein. book are not only acknowledged but greatly 

appreciated. 
The editors and associate editors acknowledge ARTHUR OSOL, 

especially the assistance of the contributors whose Editor-in-Chief 



Contents 

Page 

ABBREVIATIONS xi 

PART ONE: Drugs recognized by The United States Pharmacopeia, 
British Pharmacopoeia, International Pharmacopoeia, or The Na- 
tional Formulary 1 

PART TWO: Drugs not official in The United States Pharmacopeia, 
British Pharmacopoeia, International Pharmacopoeia, or The Na- 
tional Formulary 1523 

PART THREE: Veterinary Uses and Doses of Drugs 1935 

INDEX 2059 



ABBREVIATIONS 



A.A.A.S. — The American Association for the Advance- 
ment of Science. 
A.M.A. — The American Medical Association. 
Acta chir. Scandinav .—Acta chirurgica Scandinavica. 
Acta dermato-venereol. — Acta dermato-venerologica. 
Acta med. Scandinav. — Acta medica Scandinavica. 
Advances Enzymol. — Advances in Enzymology and 

Related Subjects of Biochemistry. 
Allg. med. Centr.-Ztg. — Allegmeine medicinische Cen- 

tral-Zeitung. 
Am. Drug. — American Druggist. 
Am. Fur Breeder — American Fur Breeder. 
Am. Heart J. — American Heart Journal. 
Am. J. Anat. — American Journal of Anatomy. 
Am. J. Bot. — American Journal of Botany. 
Am. J. Cancer. — American Journal of Cancer. 
Am. J. Clin. Path. — American Journal of Clinical 

Pathology. 
Am. J. Digest. Dis. — American Journal of Digestive 

Diseases and Nutrition. 
Am. J. Dis. Child. — American Journal of Diseases of 

Children. 
Am. J. Hyg. — American Journal of Hygiene. 
Am. J. Med. — American Journal of Medicine. 
Am. J. Med. Sc. — American Journal of Medical Sci- 
ences. 
Am. J. Obst. Gyn.— American Journal of Obstetrics 

and Gynecology. 
Am. J. Ophth. — American Journal of Ophthalmology. 
Am. J. Path. — American Journal of Pathology. 
Am. J. Pharm. — American Journal of Pharmacy. 
Am. J. Physiol. — American Journal of Physiology. 
Am. J. Psychiat. — American Journal of Psychiatry. 
Am. J. Pub. Health — American Journal of Public 

Health and the Nation's Health. 
Am. J. Roentgen. — American Journal of Roentgen- 
ology and Radium Therapy. 
Am. J. Surg. — American Journal of Surgery. 
Am. J. Syph. Gonor. Ven. Dis. — American Journal of 

Syphilis, Gonorrhea and Venereal Diseases. 
Am. J. Syph. Neurol. — American Journal of Syphilis 

and Neurology. (Now Am. J. Syph. Gonor. Ven. 

Dis.) 
Am. J. Trop. Med. — American Journal of Tropical 

Medicine. 
Am. J. Vet. Res. — American Journal of Veterinary 

Research. 
Am. Med. — American Medicine. 
Am. Perfumer — American Perfumer and Essential Oil 

Review. 
Am. Pract. Dig. Treat. — American Practitioner and 

Digest of Treatment. 
Am. Prof. Pharm. — American Professional Pharmacist. 
Am. Rev. Soviet Med. — American Review of Soviet 

Medicine. 
Am. Rev. Tuberc. — American Review of Tuberculosis. 
Am. Surg. — The American Surgeon. 
Am. Vet. Rev. — American Veterinary Review. 
Anais faculdade med. univ. S. Paulo — Anais da facul- 

dade de medicina da universidade de Sao Paulo. 
Analyst — The Analyst. 
Anesth. — Anesthesiology. 
Aneth. & Analg. — Current Researches in Anesthesia 

and Analgesia. 
Angewandte Chem. — Angewandte Chemie. 
Ann. Allergy — Annals of Allergy. 
Ann. Biochem. Exp. Med. — Annals of Biochemistry 

and Experimental Medicine. 
Ann. Chem. — Annalen der Chemie, Liebig. 



Ann. Chem. Pharm. — Annalen der Chemie und Phar- 

macie. (Now Ann. Chem.) 
Ann. chim. app. — Annali di chimica applicata. 
Ann. Chim. Phys. — Annales de Chimie et de Physique. 
Ann. d'igiene — Annali d'igiene. 
Ann. dermat. syph. — Annales de dermatologie et de 

syphiligraphie. 
Ann. Inst. Pasteur — Annales de l'lnstitut Pasteur. 
Ann. Int. Med. — Annals of Internal Medicine. 
Ann. med.-psychol. — Annales medico-psychologiques. 
Ann. N. Y. Acad. Sc. — Annals of the New York Acad- 
emy of Science. 
Ann. Otol. Rhin. Larytig. — Annals of Otology, Rhi- 

nology and Laryngology. 
Ann. Rev. Biochem. — Annual Review of Biochemistry. 
Ann. Rev. Physiol.— Annual Review of Physiology. 
Ann. Surg. — Annals of Surgery. 
Ann. Trop. Med. — Annals of Tropical Medicine and 

Parasitology. 
Ann. West. Med. Surg. — Annals of Western Medicine 

and Surgery. 
Antibiot. Chemother. — Antibiotics and Chemotherapy. 
Apoth.-Ztg. — Apotheker-Zeitung. (See also Deutsche 

Apoth.-Ztg.) 
Arbeit, pharmakol. Inst. Dorpat — Arbeiten der phar- 

makologisches Institut, Dorpat. 
Arch. Dermat. Syph. — Archives of Dermatology and 

Syphilology. 
Arch. Dis. Child. — Archives of Disease in Children. 
Arch. exp. Path. Pharm. — Archiv fur experimentelle 

Pathologie und Pharmakologie. 
Arch, farmacol. sper. — Archivo di farmacologia speri- 

mentale e scienze affini. 
Arch, farmacol. terap. — Archivio di farmacologia e 

terapeutica. 
Arch. gen. med. — Archives generates de medecine. 
Arch. ges. Physiol. — Archiv fiir die gesamte Physi- 
ologic des Menschen und der Tiere. 
Arch. Gewerbepath. Gewerbehyg. — Archiv fiir Ge- 

werbepathologie und Gewerbehygiene. 
Arch. Gyndk. — Archiv fiir Gynakologie. 
Arch. Hyg.— Archiv fiir Hygiene und Bakteriologie. 
Arch. Int. Med.- — Archives of Internal Medicine. 
Arch. Indust. Hyg. — Archives of Industrial Hygiene 

and Occupational Medicine. 
Arch, internat. pharmacodyn. therap. — Archives in- 

ternationales de pharmacodynamic et de therapie. 
Arch. mal. du coeur — Archives des maladies du cceur et 

des vaisseaux. 
Arch. Neurol. Psychiat. — Archives of Neurology and 

Psychiatry. 
Arch. Ophth. — Archives of Ophthalmology. 
Arch. Otolaryng. — Archives of Otolaryngology. 
Arch. Path. — Archives of Pathology. 
Arch. Path. Lab. Med. — Archives of Pathology and 

Laboratory Medicine. (Now Arch. Path.) 
Arch. Pediat. — Archives of Pediatrics. 
Arch, pediat. Uruguay — Archivos de pediatria del 

Uruguay. 
Arch. Pharm. — Archiv der Pharmacie. 
Arch. Phys. Med. — Archives of Physical Medicine. 
Arch. Phys. Ther. — Archives of Physical Therapy. 
Arch. Schiffs-Tropen-Hyg. — Archiv fiir Schiffs- und 

Tropen-Hygiene. 
Arch. Surg. — Archives of Surgery. 
Arch. urug. de med. — Archivos uruguayos de medi- 
cina, cirugia y especialidades. 
Aust. Vet. J. — Australian Veterinary Journal. 



XII 



ABBREVIATIONS 



Australasian J. Pharm. — Australasian Journal of Phar- 
macy. 

Australia, Council for Sc. & Indust., Res. Bull. — Aus- 
tralia, Council for Science and Industry, Research 
Bull. 

Bact. Rev. — Bacteriological Reviews. 

Beitr. Klin. Tuberk. — Beitrage zur Klinik der Tuber- 
kulose und spezifischen Tuberkulose-Forschung. 

Ber. — Berichte der deutschen chemischen Gesellschaft. 

Ber. deutsch. pharm. Ges. — Berichte der deutschen 
pharmaceutischen Gesellschaft. 

Ber. ges. Physiol. — Berichte iiber die gesamte Physi- 
ologic und experimentelle Pharmakologie. 

Berl. klin. Wchnschr. — Berliner klinische Wochen- 
schrift. (Now Klin. Wchnschr.) 

Berl. tierarztl. Wchnschr. — Berliner tierarztliche Wo- 
chenschrift. 

Biochem. J. — Biochemical Journal. 

Biochem. Ztschr. — Biochemische Zeitschrift. 

Bol. assoc. brasil. farm. — Boletim da associaqao brasil- 
eira de farmaceuticos. 

Bol. ministerio agr. — Boletim do ministerio da agri- 
cultura (Brazil). 

Boll. chim. farm. — Bollettino chimico-farmaceutico. 

Boston Med. Surg. J. — Boston Medical and Surgical 
Journal. (Now New Eng. J. Med.) 

Bot. Abs. — Botanical Abstracts. 

Bot. Centralbl. — Botanisches Centralblatt. 

Bot. Gaz. — Botanical Gazette. 

B.P. — The British Pharmacopoeia. 

B.P. Add. — Addendum to the British Pharmacopoeia. 

Brasil-med. — Brasil-medico. 

Brit. Heart J. — British Heart Journal. 

Brit. J. Derm. — British Journal of Dermatology. 

Brit. J. Anaesth. — British Journal of Anaesthesia. 

Brit. J. Exp. Path. — British Journal of Experimental 
Pathology. 

Brit. J. Ind. Med. — British Journal of Industrial 
Medicine. 

Brit. J. Ophth. — British Journal of Ophthalmology. 

Brit. J. Pharmacol. Chemother. — British Journal of 
Pharmacology and Chemotherapy. 

Brit . J. Phys. Med. — British Journal of Physical Medi- 
cine and Industrial Hygiene. 

Brit. J. Radiol. — British Journal of Radiology. 

Brit. J. Surg. — British Journal of Surgery. 

Brit. J. Tuberc. — British Journal of Tuberculosis. 

Brit. J. Urol. — British Journal of Urology. 

Brit. M. J. — British Medical Journal. 

Brit. Vet. J. — British Veterinary Journal. 

Brodil'naya Prom. — Brodil'naya Promyshlennost. 

Bruxelles-med. — Bruxelles-medical. 

Bull. A. S. H. P. — Bulletin of the American Society of 
Hospital Pharmacists. 

Bull. Acad. med. Paris — Bulletin de l'Academie de 
medecine. 

Bull. Acad. Med. Toronto — Bulletin of the Academy 
of Medicine, Toronto. 

Bull. Am. Coll. Surgeons — Bulletin of the American 
College of Surgeons. 

Bull, assoc. chim. — Bulletin de l'association des 
chimistes. 

Bull. Chem. Soc. Japan — Bulletin of the Chemical 
Society of Japan. 

Bull. gen. therap. — Bulletin general de therapeutique 
medicale, chirurgicale, obstetricale et pharma- 
ceutique. 

Bull. Health Leag. Nations — Bulletin of the Health 
Organization, League of Nations. 

Bull. Hist. Med— Bulletin of the Institute of the His- 
tory of Medicine. 

Bull. Hyg. — Bulletin of Hygiene. 

Bull. Johns Hopkins Hosp. — Bulletin of the Johns 
Hopkins Hospital. 

Bull. med. — Le bulletin medical. 



Bull. Nat. Inst. Health— Bulletin of the National In- 
stitutes of Health. 

Bull. New Eng. Med. Center — Bulletin of the New 
England Medical Center. 

Bull. N. F. Com. — Bulletin of the National Formulary 
Committee. 

Bull. N. Y. Acad. Med.— Bulletin of the New York 
Academy of Medicine. 

Bull. Pharm. — Bulletin of Pharmacy. 

Bull. Rheumat. Dis. — Bulletin on Rheumatic Diseases. 

Bull. sc. Pharmacol. — Bulletin des sciences pharma- 
cologiques. 

Bull. Sch. Med. Univ. Maryland — Bulletin of the 
School of Medicine, University of Maryland. 

Bull. soc. chim. — Bulletin de la societe chimique de 
France. 

Bull. soc. chim. Belg. — Bulletin de la societes chim- 
iques Beiges. 

Bidl. soc. chim. biol. — Bulletin de la societe de chimie 
biologique. 

Bull. soc. franc, dermat. syph. — Bulletin de la societe 
franchise de dermatologie et de syphiligraphie. 

Bull. soc. med. — Bulletins et memoires de la societe 
medicale des hopitaux de Paris. 

Bull. soc. path. exot. — Bulletin de la societe de path- 
ologie exotique et de ses filiales. 

Bull. St. Louis M. Soc. — Bulletin of the St. Louis 
Medical Society. 

Bidl. Torrey Bot. Club— Bulletin of the Torrey Bo- 
tanical Club. 

Bull. trav. soc. pharm. Bordeaux — Bulletin des travaux 
de la societe de pharmacie de Bordeaux. 

Bull. U. S. Army M. Dept— Bulletin of the United 
States Army Medical Department. 

Bull. War Med. — Bulletin of War Medicine. 

Bur. Standards J. Research — Bureau of Standards 
Journal of Research. 

Calif. & West. Med. — California and Western Medi- 
cine. 

Calif. Med. — California Medicine. 

Can. J. Comp. Med.— Canadian Journal of Compara- 
tive Medicine and Veterinary Science. 

Can. J. Research — Canadian Journal of Research. 

Can. Med. Assoc. J. — Canadian Medical Association 
Journal. 

Can. Pharm. J. — Canadian Pharmaceutical Journal. 

Can. Pub. Health J. — Canadian Public Health Journal. 

Can. Vet. Rec. — Canadian Veterinary Record. 

Cancer Res. — Cancer Research. 

Centralbl. med. Wissensch. — Centralblatt fur die medi- 
zinischen Wissenschaften. 

Cereal Chem. — Cereal Chemistry. 

Chem. Abs. — Chemical Abstracts. 

Chem. Centralbl. — Chemisches Centralblatt. 

Chem. Drug. — The Chemist and Druggist. 

Chem. Eng. News — Chemical and Engineering News. 

Chem. Industries — Chemical Industries. 

Chem. Met. Eng. — Chemical and Metallurgical Engi- 
neering. 

Chem. News — Chemical News and Journal of In- 
dustrial Science. 

Chem. Rev. — Chemical Reviews. 

Chem. Trade J. — Chemical Trade Journal and Chem- 
ical Engineer. 

Ckem.-Ztg. — Chemiker-Zeitung. 

Chimica e I'industria Milan — La chimica e l'industria, 
Milan. 

Chinese J. Physiol. — Chinese Journal of Physiology. 

Chinese M. J. — Chinese Medical Journal. 

Cincinnati J. Med.— Cincinnati Journal of Medicine. 

Cincinnati M. J. — Cincinnati Medical Journal. 

Cleveland Clin. Quart. — Cleveland Clinic Quarterly. 

Cleveland M. J. — Cleveland Medical Journal. 

Clin. J. — Clinical Journal. 

Clin. Med. — Clinical Medicine. 

Clin. Proc. — Clinical Proceedings. 



ABBREVIATIONS 



XIII 



Clin. Sc. — Clinical Science. 

Clinics — Clinics. 

Colorado Med. — Colorado Medicine. (Now Rocky 

Mountain M. J.) 
Compt. rend. acad. sc. — Comptes rendus hebdoma- 

daires des seances de l'academie des sciences. 
Compt. rend. soc. biol. — Comptes rendus des seances 

de la societe de biologic 
Confinia Neurol. — Confinia Neurologica. 
Connecticut State M. /.—Connecticut State Medical 

Journal. 
Cornell Vet. — The Cornell Veterinarian. 
Dansk Tids. Farm. — Dansk Tidsskrift for Farmaci. 
Delaware S. M. J. — Delaware State Medical Journal. 
Dental Rec. — Dental Record. 
Dental Survey — Dental Survey. 
Dentistry — Dentistry, a Digest of Practice. 
Derm. Wchnschr. — Dermatologische Wochenschrift. 
Derm. Ztschr. — Dermatologische Zeitschrift. 
Deutsche Apoth.-Ztg. — Deutsche Apotheker-Zeitung. 
Deutsche med. 7.— Deutsches medizinisches Journal. 
Deutsche med. Wchnschr. — Deutsche medicinische 

Wochenschrift. 
Deutsche Mil. — Deutsche Militararzt. 
Deutsche tierarztl. Wochenschr. — Deutsche tierarzt- 

liche Wochenschrift. 
Deutsche zahnarztl. Wchnschr. — Deutsche zahnarzt- 

liche Wochenschrift. 
Deutsche Ztschr. ges. gerichtl. Med. — Deutsche Zeit- 
schrift fur die gesamte gerichtliche Medizin. 
Deutsches Arch. klin. Med. — Deutsches Archiv fur 

klinische Medizin. 
Dis. Nerv. Syst. — Diseases of the Nervous System. 
Drug. Circ. — Druggists Circular. 
Drug Cosmet. Ind. — Drug and Cosmetic Industry. 
East African M. J. — East African Medical Journal. 
Edinburgh M. J. — Edinburgh Medical Journal. 
Endocrinology — Endocrinology. 
Enzymologia — Enzymologia. 
Ergebn. Enzymforsch. — Ergebnisse der Enzymfor- 

schung. 
Exp. Med. & Surg. — Experimental Medicine and 

Surgery. 
Eye, Ear, Nose & Throat Monthly — Eye, Ear, Nose 

and Throat Monthly. 
Farm. Revy — Farmacevtisk Revy. 
Farmakol. i Toksikol. — Farmakologiia i Toksikologiia. 
Fed. Proc. — Federation Proceedings. 
Fettchem. Umschau — Fettchemische Umschau. (Now 

Fette und Seifen.) 
Fette und Seifen — Fette und Seifen. 
Folia Medica — Folia Medica, Naples. 
Food Res. — Food Research. 
Fortschr. Med. — Fortschritte der Medizin. 
Fortschr. Ther. — Fortschritte der Therapie. 
Fr. — French Codex. 
Gastroenterology — Gastroenterology. 
Gaz. chim. ital.- — Gazzetta chimica italiana. 
Gaz. med. de France — Gazette medicale de France 

et des pays de langue franchise. 
Gaz. med. Paris — Gazettes medicale, Paris. 
Ger. — German Pharmacopoeia. 
Geriatrics — Geriatrics. 
Guy's Hosp. Rep. — Guy's Hospital Reports. 
Heart — Heart. 
Heilkunde — Heilkunde. 
Helv. Chim. Acta — Helvetica Chimica Acta. 
Helv. Physiol. Pharm. Acta — Helvetica Physiologica et 

Pharmacologica Acta. 
Herbarist — Herbarist. 
Human Fert. — Human Fertility. 
Hyg. Lab. Bull. — Hygienic Laboratory Bulletin. (Now 

Bull. Nat. Inst. Health.) 
Illinois M. J. — Illinois Medical Journal. 
Ind. Chemist — Industrial Chemist and Chemical 

Manufacturer. 



Ind. Eng. Chem. — Industrial and Engineering Chem- 
istry. 

Ind. Eng. Chem., Anal. Ed. — Industrial and Engi- 
neering Chemistry, Analytical Edition. 

Ind. Med. — Industrial Medicine. 

Indian J. Med. Res. — Indian Journal of Medical Re- 
search. 

Indian J. Pharm. — Indian Journal of Pharmacy. 

Indian Med. Gaz. — Indian Medical Gazette. 

Indian Vet. J. — The Indian Veterinary Journal. 

Indiana State M. A. J. — Indiana State Medical Asso- 
ciation Journal. 

Internat. Clin. — International Clinics. (Now New 
Internat. Clin.) 

Internat. J. Med. Surg. — International Journal of 
Medicine and Surgery. 

Internat. Med. Digest — International Medical Digest. 

Internat. Rec. Med. — International Record of Medi- 
cine and General Practice Clinics. 

It. — Italian Pharmacopoeia. 

J.A.CS. — Journal of the American Chemical Society. 

/. A. Dent. A. — Journal of the American Dental 
Association. 

/. A. Dietet. A. — Journal of the American Dietetic 
Association. 

/. A. Inst. Homeopathy — Journal of the American 
Institute of Homeopathy. 

J. A.M. A. — Journal of the American Medical Asso- 
ciation. 

J. A. M. Women's A. — Journal of the American Medi- 
cal Women's Association. 

J.A.O.A.C. — Journal of the Association of Official 
Agricultural Chemists. 

/. A. Ph. A. — Journal of the American Pharmaceu- 
tical Association. 

J. A. Ph. A., Prac. Ed. — Journal of the American 
Pharmaceutical Association, Practical Edition. 

J.A.V.M.A. — Journal of the American Veterinary 
Medical Association. 

/. Agric. Food Chem. — Journal of Agricultural and 
Food Chemistry. 

/. Agric. Res. — Journal of Agricultural Research. 

/. Agric. Sc. — The Journal of Agricultural Science. 

/. Albert Einstein Med. Center — Journal of the Albert 
Einstein Medical Center. 

/. Allergy— The Journal of Allergy. 

/. Anat. — Journal of Anatomy. 

/. Ani. Sc. — Journal of Animal Science. 

/. Bad. — Journal of Bacteriology. 

J. Biol. Chem. — Journal of Biological Chemistry. 

/. Bone Joint Surg. — Journal of Bone and Joint 
Surgery. 

/. Calif. State Dent. A. — Journal of the California 
State Dental Association. 

J. Can. Dent. A. — Journal of the Canadian Dental 
Association. 

/. Chem. Educ. — Journal of Chemical Education. 

/. Chem. Ind. — Journal of Chemical Industry (Mos- 
cow). 

/. Chem. S. — Journal of the Chemical Society. 

/. Chemother. — Journal of Chemotherapy. 

/. chim. phys. — Journal de chimie physique. 

/. Clin. Endocrinol. — Journal of Clinical Endocrinol- 
ogy. 

/. Clin. Inv. — Journal of Clinical Investigation. 

J. Clin. Nutrition — Journal of Clinical Nutrition. 

J. Comp. Path. Therap. — The Journal of Comparative 
Pathology and Therapeutics. 

/. Council Sci. Ind. Res. — Journal of the Council for 
Scientific and Industrial Research. 

/. Cutan. Dis. — Journal of Cutaneous Diseases includ- 
ing Syphilis. 

J. Dairy Sc. — Journal of Dairy Science. 

/. Dent. Research — Journal of Dental Research. 

/. Econ. Entomol. — Journal of Economic Entomology. 

/. Endocrinol. — Journal of Endocrinology. 



XIV 



ABBREVIATIONS 



/. Exp. Med. — Journal of Experimental Medicine. 

/. Gen. Client. (US.S.R.)— Journal of General Chem- 
istry (U.S.S.R.). 

J. Gen. Microbiol. — Journal of General Microbiology. 

/. Gen. Physiol. — Journal of General Physiology. 

J. Geront. — Journal of Gerontology. 

J. Hygiene — Journal of Hygiene. 

/. Immunol. — Journal of Immunology. 

/. Ind. Hyg. Toxicol. — Journal of Industrial Hygiene 
and Toxicology. 

/. Indian Chem. S. — Journal of the Indian Chemical 
Society. 

/. Indian Inst. Sc. — Journal of the Indian Institute of 
Science. 

/. Indian M. A. — Journal of the Indian Medical 
Association. 

/. Indiana M. A. — Journal of the Indiana State 
Medical Association. 

/. Inject. Dis. — Journal of Infectious Diseases. 

/. Internat. Col. Surg. — Journal of the International 
College of Surgeons. 

J. Invest. Dermat. — Journal of Investigative Derma- 
tology. 

/. Iowa M. Soc. — Journal of Iowa State Medical 
Society. 

/. Lab. Clin. Med. — Journal of Laboratory and Clini- 
cal Medicine. 

J. -Lancet — Journal-Lancet. 

/. Laryng. Otol. — Journal of Laryngology and Otol- 
ogy. 

J. Linn. Soc. — Journal of the Linnaean Society. 

J. M. A. Alabama — Journal of the Medical Associa- 
tion of the State of Alabama. 

J. M. A. Georgia — Journal of the Medical Association 
of Georgia. 

/. M. Soc. New Jersey — Journal of the Medical So- 
ciety of New Jersey. 

/. Maine M. A. — Journal of the Maine Medical Asso- 
ciation. 

J. mid. chirurg. prat. — Journal de medecine et de 
chirurgie pratiques. 

/. mid. Lyon — Le journal de medecine de Lyon. 

/. mid. Paris — Journal de medecine de Paris. 

J. Ment. Sc. — Journal of Mental Science. 

J. Michigan M. Soc. — Journal of Michigan State 
Medical Society. 

/. Missouri M. A. — Journal of Missouri State Medical 
Association. 

/. Mt. Sinai Hosp. — Journal of the Mount Sinai Hos- 
pital, New York. 

/. Nat. Cancer Inst. — Journal of the National Cancer 
Institute. 

J. Nat. M. A. — Journal of the National Medical 
Association. 

/. Nat. Malaria Soc. — Journal of the National Malaria 
Society. 

/. Nerv. Ment. Dis. — Journal of Nervous and Mental 
Disease. 

/. Neurophysiol. — Journal of Neurophysiology. 

/. Neurosurg. — Journal of Neurosurgery. 

/. Nutrition — The Journal of Nutrition. 

/. Obst. Gyn. Br. Emp. — Journal of Obstetrics and 
Gynaecology of the British Empire. 

/. Oil & Colour Chem. Assoc. — Journal of the Oil 
and Colour Chemists' Association. 

/. Omaha Mid-West Clin. Soc. — Journal of the Omaha 
Mid-West Clinical Society. 

/. Oral Surg. — Journal of Oral Surgery. 

/. Org. Chem. — Journal of Organic Chemistry. 

/. Parasitol. — Journal of Parasitology. 

/. Parenteral Therapy — Journal of Parenteral Ther- 
apy. 

/. Path. Bad. — Journal of Pathology and Bacteriol- 
ogy. 

/. Pediatr. — Journal of Pediatrics. 



J. pharm. Alsace Lorraine — Journal de pharmacie 
d'Alsace et de Lorraine. 

J. pharm. Belg. — Journal de pharmacie de Belgique. 

/. pharm. chim. — Journal de pharmacie et de chimie. 

/. Pharm. Pharmacol. — The Journal of Pharmacy and 
Pharmacology. 

J. Pharm. Soc. Japan — Journal of the Pharmaceutical 
Society of Japan. 

/. Pharmacol. — Journal of Pharmacology and Experi- 
mental Therapeutics. 

/. Phys. Chem. — Journal of Physical Chemistry. 

/. Physiol. — Journal of Physiology. 

/. prakt. Chem. — Journal fvir praktische Chemie. 

/. Prevent. Med. — Journal of Preventive Medicine. 

J. Proc. Roy. Soc. N. S. Wales — Journal and Proceed- 
ings of the Royal Society of New South Wales. 

/. Roy. Army Med. Corps — Journal of the Royal 
Army Medical Corps. 

/. Roy. Soc. W. Australia — Journal of the Royal So- 
ciety of Western Australia. 

/. Russ. Phys. Chem. S. — Journal of the Russian 
Physical-Chemical Society. 

/. Soc. Chem. Ind. — Journal of the Society of Chemi- 
cal Industry. 

/. South African V. M. A. — The Journal of the South 
African Veterinary Medical Association. 

/. Thoracic Surg.- — Journal of Thoracic Surgery. 

/. Trop. Med. Hyg. — Journal of Tropical Medicine 
and Hygiene. 

/. Urol. — The Journal of Urology. 

J. Ven. Dis. Inform. — Journal of Venereal Disease 
Information. 

Jahresber. Pharm. — Jahresbericht der Pharmazie. 

Jap. J. Med. Sc. — Japanese Journal of Medical Sci- 
ences. 

Kentucky M. J. — Kentucky Medical Journal. 

Klin. Monatsbl. Augen. — Klinische Monatsblatter fur 
Augenheilkunde. 

Klin.-therap. Wchnschr. — Klinisch-therapeutische 
Wochenschrift. 

Klin. Wchnschr. — Klinische Wochenschrift. 

Kunststoffe — Kunststoffe: Zeitschrift fur Erzeugung 
und Venvendung veredelter oder chemisch herges- 
tellter Stoffe. 

Lahey Clin. Bull.- — Lahey Clinic Bulletin. 

Lancet — The Lancet. 

Laryng. — Laryngoscope. 

Laval mid. — Laval medical. 

L'Union pharm. — L'Union pharmaceutique. 

M. S. C. Vet. — The M. S. C. Veterinarian. 

Med. Ann. District Columbia — Medical Annals of the 
District of Columbia. 

Med. Bl. — Medicinische Blaetter. 

Med. Bull. Vet. Admin.— Medical Bulletin of the 
Veterans' Administration. 

Med. Clin. North America — The Medical Clinics of 
North America. 

Med. J. Australia — Medical Journal of Australia. 

Med. Klin. — Medizinische Khnik. 

Med. Press— Medical Press and Circular. 

Med. Rec. — Medical Record. 

Med. Rund. — Medizinische Rundschau. 

Med. Times— Medical Times. 

Medecine — La Medecine. 

Medicine — Medicine: Analytical Reviews of General 
Medicine, Neurology and Pediatrics. 

Merck Rep— The Merck Report. 

Merck's Jahresber. — Merck's Jahresbericht uber Neu- 
erungen auf den Gebieten der Pharmakotherapie 
und Pharmazie. 

Mfg. Chemist— The Manufacturing Chemist. 

Mfg. Perfumer — The Manufacturing Perfumer. 
(Merged with Mfg. Chemist.) 

Mikrochemie — Mikrochemie. 

MU. Surg. — Military Surgeon. 

Minn. Med. — Minnesota Medicine. 



ABBREVIATIONS 



xv 



Missouri Agric. Exp. Sta. Res. Bull. — Missouri Agri- 
cultural Experiment Station Research Bulletin. 
Missouri Med. — Missouri Medicine. 
Mitt. med. Akad. Kioto — Mitteilungen aus der medi- 

zinischen Akademie zu Kioto. 
Monatsh. Chetn. — Monatshefte fur Chemie und ver- 

wandte Teile anderer Wissenschaften. 
Monatsh. f. Vet.-tned. — Monatshefte fur Veterinar- 

medizin. 
Monatsh. prakt. Tierheilk. — Monatshefte fiir prak- 

tische Tierheilkunde. 
Monatsschr. Geburtsh. Gyn'dk. — Monatsschrift fiir 

Geburtshiilfe und Gynakologie. 
Munch, med. Wchnschr. — Munchener medizinische 

Wochenschrift. 
N. Carolina M. J. — North Carolina Medical Journal. 
N.F. — The National Formulary, Tenth Edition. 
N. Y. State J. Med. — New York State Journal of 

Medicine. 
Nat. Res. Council Bull. — National Research Council 

Bulletin. 
Nature — Nature. 
Nederland. Tijdschr. Pharm. — Nederlandsch Tijd- 

schrift voor Pharmacie, Chemie en Toxicologic 
New Eng. J. Med. — New England Journal of Medi- 
cine. 
New Internat. Clin. — New International Clinics. 
New Orleans Med. Surg. J. — New Orleans Medical 

and Surgical Journal. 
North Am. Vet.- — The North American Veterinarian. 
Northwest Med. — Northwest Medicine. 
Nouv. Rem. — Nouveaux Remedes. 
Nutrition Rev. — Nutrition Reviews. 
Obst. Gyn. — Obstetrics and Gynecology. 
Occup. Med. — Occupational Medicine. 
Oesterr. Chem.-Ztg. — Oesterreichische Chemiker- 

Zeitung. (Now Wien. Chem.-Ztg.) 
Ohio State M. J. — Ohio State Medical Journal. 
Oil and Fat Ind. — Oil and Fat Industries. (Now Oil 

and Soap.) 
Oil and Soap — Oil and Soap. 
Oral Surg., Oral Med., Oral Path— Oral Surgery, Oral 

Medicine and Oral Pathology. 
Orient. J. Dis. Infants — Oriental Journal of Diseases 

of Infants. 
Pediatr. — Pediatrics. 

Pennsylvania M. J. — Pennsylvania Medical Journal. 
Perf. Ess. Oil Rec. — Perfumery and Essential Oil 

Record. 
Pest, med.-chirurg. Presse — Pester medicinisch-chirur- 

gische Presse. 
Pharm. Acta Helv. — Pharmaceutica Acta Helvetiae. 
Pharm. Arch. — Pharmaceutical Archives. 
Pharm. Era — Pharmaceutical Era. 
Pharm. J. — Pharmaceutical Journal. 
Pharm. Monatsh. — Pharmazeutische Monatshefte. 
Pharm. Presse — Pharmazeutische Presse. 
Pharm. Rev. — Pharmaceutical Review. 
Pharm. Rund. — Pharmaceutische Rundschau. 
Pharm. Tijdschr. — Pharmaceutisch Tijdschrift voor 

Nederlandsch-Indie. 
Pharm. Weekblad — Pharmaceutisch Weekblad. 
Pharm. Zentr. — Pharmaceutische Zentralhalle fiir 

Deutschland. 
Pharm. Ztg. — Pharmaceutische Zeitung. 
Pharmacol. Rev. — Pharmacological Reviews. 
Phila. Med. — Philadelphia Medicine. 
Philippine J. Sc. — Philippine Journal of Science. 
Physiol. Rev. — Physiological Reviews. 
Pittsburgh Med. Bull— Pittsburgh Medical Bulletin. 
Plast. Reconstruct. Surg. — Plastic and Reconstructive 

Surgery. 
Postgrad. Med. — Postgraduate Medicine. 
Poultry Sc. — Poultry Science. 
Pract . — Practitioner. 
Pract. Drug. — Practical Druggist. 



Praktika Akad. Athenon — Praktika Akademia 
Athen5n. 

Prensa med. Argent. — La prensa medica Argentina. 

Prensa med. Mexicana — Prensa medica Mexicana. 

Presse med. — Presse medicale. 

Proc. A. Diabetes A. — Proceedings of the American 
Diabetes Association. 

Proc. A. Ph. A. — Proceedings of the American Phar- 
maceutical Association. 

Proc. Centr. Soc. Clin. Res. — Proceedings of the 
Central Society for Clinical Research. 

Proc. Chem. S. — Proceedings of the Chemical Society. 

Proc. Helminthol. Soc. — Proceedings of the Helmin- 
thological Society. 

Proc. Imp. Acad. Tokyo- — Proceedings of the Im- 
perial Academy (Tokyo). 

Proc. Indian Acad. Sc. — Proceedings of the Indian 
Academy of Sciences. 

Proc. Indiana Vet. Med. Assoc. — Proceedings of the 
Indiana Veterinary Medical Association. 

Proc. Int. Congr. PI. Sc. — Proceedings of the Inter- 
national Congress of Plant Science. 

Proc. Mayo — Proceedings of the Staff Meetings of 
the Mayo Clinic. 

Proc. Nat. Acad. Sc. — Proceedings of the National 
Academy of Science. 

Proc. N. J. Ph. A. — Proceedings of the New Jersey 
Pharmaceutical Association. 

Proc. Penn. Ph. A. — Proceedings of the Pennsylvania 
Pharmaceutical Association. 

Proc. Roy. Soc. London — Proceedings of the Royal 
Society, London. 

Proc. Roy. Soc. Med. — Proceedings of the Royal So- 
ciety of Medicine. 

Proc. S. Dakota Acad. Sc. — Proceedings of the South 
Dakota Academy of Sciences. 

Proc. S. Exp. Biol. Med. — Proceedings of the Society 
for Experimental Biology and Medicine. 

Progres med.- — Le progres medical. 

Psych. Quart. — Psychiatric Quarterly. 

Psychosom. Med. — Psychosomatic Medicine. 

Pub. Health Rep.— Public Health Reports. 

Puerto Rico J. Pub. Health — Puerto Rico Journal of 
Public Health and Tropical Medicine. 

Quart. Bull. Northwest. U. Med. Sch. — Quarterly Bul- 
letin of Northwestern University Medical School. 

Quart. J. Exp. Physiol. — Quarterly Journal of Ex- 
perimental Physiology. 

Quart. J. Med.— Quarterly Journal of Medicine. 

Quart. J. P. — Quarterly Journal of Pharmacy and 
Pharmacology. 

Quart. J. Stud. Alcohol — Quarterly Journal of Studies 
on Alcohol. 

Queensland Agr. J. — Queensland Agricultural Journal. 

Radiology — Radiology. 

Rec. trav. chim. — Recueil des travaux chimiques des 
Pays-Bas. 

Rev. assoc. brasil. farm. — Revista da associaqao brasi- 
leira de farmaceuticos. 

Rev. brasil. med. farm.— Revista brasileira de medi- 
cina e farmacia. 

Rev . Canad. Biol. — Revue Canadienne de Biologic 

Rev. chim. ind. — Revista de chimica industrial (Rio 
de Janeiro). 

Rev. din. espan. — Revista clinica espanola. 

Rev. filipina med. farm. — Revista filipina de medicina 
y farmacia. 

Rev. flora med. — Revista de flora medicinal (Rio de 
Janeiro). 

Rev. Gastroenterol. — The Review of Gastroenterology. 

Rev. gen. Clin. Therap. — Revue generale de Clinique 
et de Therapeutique. 

Rev. med. hyg. trop. — Revue de medecine et d'hy- 
giene tropicales. 

Rev. med. Liege — Revue medicale de Liege. 



XVI 



ABBREVIATIONS 



Rev. med. Suisse Rom. — Revue medicale de la Suisse 
Romande. 

Rev. neurol. — Revue neurologique. 

Rev. quim. pura aplic. — Revista de quimica pura e 
aplicada. 

Rev. therap. med.-chirurg. — Revue de therapeutique 
medico-chirurgicale. 

Riechstoff Ind. — Riechstoff Industrie. 

Rif. med. — La Riforma medica. 

Rocky Mountain M. J. — Rocky Mountain Medical 
Journal. 

Royal Col. Phys. Rep. Edinburgh — Royal College of 
Physicians Laboratory Reports, Edinburgh. 

5. Dakota J. M. Pharm.— South Dakota Journal of 
Medicine and Pharmacy. 

Sang — Le sang. 

Sao Paulo med. — Sao Paulo medico. 

Schim. Rep. — Schimmel & Co., Annual Report. 

Schweiz. Apoth.-Ztg. — Schweizerische Apotheker- 
Zeitung. 

Schweiz. Arch. Tierheilk. — Schweizerische Archiv fiir 
Tierheilkunde. 

Schweiz. med. Wchnschr. — Schweizerische medizinische 
Wochenschrift. 

Schweiz. naturforsch. Gesell. — Schweizerische natur- 
forschende Gesellschaft. 

Schweiz. Wchnschr. Pharm. — Schweizerische Woch- 
enschrift fiir Pharmacie. 

Sci. Monthly — Scientific Monthly. 

Science — Science. 

Scientia Pharm. — Scientia Pharmaceutica. 

Seifensieder-Ztg. — Seifensieder-Zeitung. 

Semaine med. — Semaine medicale. 

Semana medica — La Semana medica. 

Skandinav. Arch. Physiol. — Skandinavisches Archiv 
fiir Physiologie. 

Soap, Perf. & Cos. — Soap, Perfumery and Cosmetics 
Trade Journal. 

South African J. Med. Sc. — South African Journal 
of Medical Sciences. 

South. M. J. — Southern Medical Journal. 

South. Med. Surg. — Southern Medicine and Surgery. 

Sp. — Spanish Pharmacopoeia. 

Stanford M. Bull. — Stanford University Medical Bul- 
letin. 

Siidd. Apoth.-Ztg. — Suddeutsche Apotheker-Zeitung. 

Surg. Clinics N. America — Surgical Clinics of North 
America. 

Surg. Gynec. Obst. — Surgery, Gynecology and Ob- 
stetrics with International Abstract of Surgery. 

Surgery — Surgery. 

Texas Repts. Biol. Med. — Texas Reports on Biology 
and Medicine. 

Texas State J. Med. — Texas State Journal of Medi- 
cine. 

Ther. Geg. — Therapie de Gegenwart. 

Therap. Gaz. — Therapeutic Gazette. 

Therap. Halbmonatsh. — Therapeutische Halbmonat- 
shefte. 

Therap. Monatsh. — Therapeutische Monatshefte. 

Tierdrztl. Rundsch. — Tier'arztliche Rundschau. 

Tohoku J. Exp. Med. — Tohoku Journal of Experi- 
mental Medicine. 

Trade Corres. — Trade Correspondence of the Food 
and Drug Administration. 

Trans. A. Am. Phys. — Transactions of the Association 
of American Physicians. 

Trans. Am. Acad. Ophth. — Transactions of the Ameri- 
can Academy of Ophthalmology and Oto- 
laryngology. 

Trans. Am. Inst. Chem. Engrs. — Transactions of the 
American Institute of Chemical Engineers. 

Trans. Am. Laryng. Rhin. Otol. Soc. — Transactions 
of the American Laryngological, Rhinological and 
Otological Society. 



Trans. Am. Neurol. A. — Transactions of the American 
Neurological Association. 

Trans. Chem. Soc. — Transactions of the Chemical 
Society of London. 

Trans. Roy. Soc. Trop. Med. Hyg. — Transactions 
of the Royal Society of Tropical Medicine and 
Hygiene. 

Trans. South. Surg. Gynec. A. — Transactions of the 
Southern Surgical and Gynecological Association. 

Trans. Stud. Coll. Phys. — Transactions and Studies of 
the College of Physicians of Philadelphia. 

Trop. Dis. Bull. — Tropical Diseases Bulletin. 

U. S. Armed Forces M. J. — United States Armed 
Forces Medical Journal. 

U. S. Army Vet. Bull. — United States Army Veteri- 
nary Bulletin. 

U.S.D. — The United States Dispensatory. 

U.S.D.A. Farmers' Bull. — United States Department 
of Agriculture Farmers' Bulletin. 

U.S.D.A. Leaflet. — United States Department of Agri- 
culture Leaflet. 

US.D.A. Yearbook — United States Department of 
Agriculture Yearbook. 

U. S. Nav. M. Bull— United States Naval Medical 
Bulletin. 

U.SJP. — The United States Pharmacopeia, Fifteenth 
Revision. 

Ugeskr. f. laeger — Ugeskrift for laeger. 

Union med. Canada — Union medicale du Canada. 

Univ. Hosp. Bull. Ann Arbor — University Hospital 
Bulletin (Ann Arbor). 

Univ. Mich. M. Bull. — University of Michigan Medical 
Bulletin. 

Univ. Penn. Bull. Vet. Ext. Quart. — University of 
Pennsylvania Bulletin Veterinary Extension Quar- 
terly. 

Univ. Penn. M. Bull. — University of Pennsylvania 
Medical Bulletin. 

Upsala lakaref. fdrh. — Upsala lakareforenings for- 
handlingar. 

Urol. Cutan. Rev. — Urologic and Cutaneous Review. 

Ven. Dis. Inform. — Venereal Disease Information. 

Vet. Bull. Lederle — Veterinary Bulletin (Lederle). 

Vet. J. — Veterinary Journal. 

Vet. Med. — Veterinary Medicine. 

Vet. Rec. — The Veterinary Record. 

Vierteljahrsschr. prakt. Pharm. — Vierteljahrsschrift 
fiir praktische Pharmazie. (Merged into Arch. 
Pharm.) 

Virchows Arch. path. Anat. — Virchows Archiv fiir 
pathologische Anatomie und Physiologie und fiir 
klinische Medizin. 

Virginia Med. Month. — Virginia Medical Monthly. 

Vlaam's Diergeneesk. Tijdschr. — Vlaam's Diergenees- 
kunde Tijdschrift. 

War Med. — War Medicine. 

West. J. Surg. Obst. Gyn. — Western Journal of Sur- 
gery, Obstetrics and Gynecology. 

West Virg. M. J. — West Virginia Medical Journal. 

Wien. Chem.-Ztg. — Wiener Chemiker-Zeitung. 

Wien. klin. Wchnschr. — Wiener klinische Wochen- 
schrift. 

Wien. med. Bl. — Wiener medizinische Blatter. (Now 
Med. Bl.) 

Wien. tierdrztl. Monatsschr. — Wiener tierarztliche 
Monatsschrift. 

Wisconsin Exp. Sta. Ann. Rep. Bull. — Wisconsin Ex- 
periment Station Annual Report Bulletin. 

Wisconsin M. J. — Wisconsin Medical Journal. 

Yale J. Biol. Med. — Yale Journal of Biology and 
Medicine. 

Year-book Pharm. — Year-book of Pharmacy and 
Transactions of British Pharmaceutical Confer- 
ence. 

Zentralbl. Bakt. — Zentralblatt fiir Bakteriologie, 
Parasitenkunde und Infektionskrankheiten. 



ABBREVIATIONS 



XVII 



Zentralbl. Chir. — Zentralblatt fur Chirurgie. 
Zentralbl. Gyntik. — Zentralblatt fur Gynakologie. 
Zentralbl. Haut-Geschlechtskrank. — Zentralblatt fur 

Haut- und Geschlechtskrankheiten sowie deren 

Grenzgebiete. 
Zentralbl. inn. Med. — Zentralblatt fiir innere Medizin. 
Ztschr. anal. Chem. — Zeitschrift fiir analytische 

Chemie. 
Ztschr. Biol. — Zeitschrift fiir Biologic 
Ztschr. exp. Path. Titer. — Zeitschrift fiir experimen- 

telle Pathologie und Therapie. 
Ztschr. ges. exp. Med. — Zeitschrift fur die gesamte ex- 

perimentelle Medizin. 
Ztschr. ges. Neurol. Psych. — Zeitschrift fiir die 

gesamte Neurologie und Psychiatric 
Ztschr. Hyg. Infektionskr. — Zeitschrift fiir Hygiene 

und Infektionskrankheiten. 
Ztschr. Immun. exp. Ther. — Zeitschrift fiir Immuni- 

tatsforschung und experimentelle Therapie. 



Ztschr. Infektionskr. — Zeitschrift fiir Infektionskrank- 
heiten, parasitare Krankheiten und Hygiene der 
Haustierc 

Ztschr. Kinderh. — Zeitschrift fiir Kinderheilkunde. 

Ztschr. klin. Med. — Zeitschrift fiir klinische Medizin. 

Ztschr. Kreislauf. — Zeitschrift fiir Kreislaufforschung. 

Ztschr. Laryng. Rhin. — Zeitschrift fiir Laryngologie, 
Rhinologie, Otologie und ihre Grenzgebiete. 

Ztschr. Naturforsch. — Zeitschrift fiir Naturforschung. 

Ztschr. physiol. Chem. — Zeitschrift fiir physiologische 
Chemie. 

Ztschr. Untersuch. Nahr. Genussm. — Zeitschrift fiir 
Untersuchung der Nahrungs- und Genussmittel, 
sowie der Gebrauchsgegenstande. (Now Ztschr. 
Untersuch. Lebensm.) 

Ztschr. Untersuch. Lebensm. — Zeitschrift fiir Unter- 
suchung der Lebensmittel. 

Ztschr. Vitaminjorsch. — Zeitschrift fiir Vitaminfor- 
schung. 



THE DISPENSATORY 

OF 

THE UNITED STATES 



PART ONE: Drugs recognized by The United States 

Pharmacopeia, British Pharmacopoeia, International 

Pharmacopoeia or The National Formulary 



ACACIA. U.S.P., B.P. 

Gum Arabic, [Acacia] 

"Acacia is the dried gummy exudate from the 
stems and branches of Acacia Senegal (Linne) 
Willdenow, or of other related African species of 
Acacia (Fam. Leguminosa) ." U.S. P. The B.P. 
definition is the same except that it does not 
specify the geographical origin. 

Gum Acacia. Acaciae Gurami; Gummi Africanum; Gummi 
Mimosae; Gummi Arabicum. Fr. Gomme arabique; Gomme 
de Senegal. Ger. Arabisches Gummi; Akazien Gummi; 
Senegalgummi. It. Gomma Arabica; Gomma del Senegal. 
Sp. Goma de acacia; Goma Ardbiga; Goma del Senegal. 

The name Acacia was employed by the ancient 
Greeks to designate the gum tree of Egypt, and 
has been appropriately applied to the genus in 
which that plant is included. Gum Arabic is re- 
corded by Herodotus (5th century B.C.) as being 
used by the ancient Egyptians as an adhesive. Its 
use in medicine is mentioned in several of the 
Egyptian papyri. Hippocrates refers to it in medi- 
cal works published between 450-350 B.C. 

The genus Acacia includes more than 500 spe- 
cies of tropical trees and shrubs, many of which 
have been of considerable economic importance 
as sources of gums, tannins, timber, dyes and 
perfumes. The Ark of the Covenant and the 
furniture of the Tabernacle are said to have been 
made from timber yielded by Acacia Seyal, the 
Shittim wood tree of the Bible. The same wood 
was made into coffins for the burial of the 
Egyptian kings. 

The acacias thrive in the forests of northern 
Africa, occupying a zone stretching across the 
continent from Abyssinia in the east to Senegal 
in the west and chiefly between the 12 th and 13 th 
degree of latitude. The most important of the 
gum-yielding acacias is the official A. Senegal 
(Linne) Willd. This is a small tree rarely exceed- 
ing a height of 6 m., with a grayish bark, bipin- 
nate leaves, dense spikes of small yellow flowers, 
and broad pods containing 5 or 6 seeds. It forms 
large forests in western Africa, north of the river 
Senegal, and is abundant in eastern Africa, Khor- 



1 



dofan, and southern Nubia. It is known by the 
natives of Senegambia as Verek and of Khordofan 
as Hashab. 

Nearly all species of acacia growing in Africa 
yield gum. The commercial Somali gum, which is 
usually of fair quality, is yielded by A. glauco- 
phylla Steud. and A. abyssinica Hochst., shrubs 
growing in Abyssinia and the Somali country. 
The following species yield a gum having a brown- 
ish or reddish color, and hence are less valuable, 
viz., African A. arabica Willd. (Amrad gum), A. 
stenocarpa Hochst. ex A. Rich., A. Seyal Del. and 
A. Ehrenbergiana Hayne. It would appear from 
the studies of Rangaswami {Indian J. Pharm., 
1942, 4, 128) that the pale yellow gum from 
A. arabica produced in S. India nearly approaches 
that of A. Senegal in quality and could be used 
as a substitute for it. Inferior gums are yielded 
also by the following: A. horrida Willd., which 
furnishes the so-called Cape gum, distinguished 
by being very brittle and yielding a less adhesive 
mucilage. Talca or Sennarr gum is derived from 
A. Seyal Delile and A. stenocarpa Hochst. ex A. 
Rich. This gum has a greenish tinge and yields 
a ropy mucilage. Amritsar gum is obtained from 
A. modesta Wall. It occurs in large brown tears 
and like A. arabica is used in calico printing. 
Mogadore gum, derived from A. gummi f era 
Willd., occurs in dark brown tears which are little 
fissured. Australian gum has usually a reddish 
color, said to be due to the presence of tannin, 
although some specimens are light in color and 
scarcely distinguishable from acacia. This gum is 
also called Wattle gum or Australian gum, and is 
derived from the Golden Wattle Acacia (A. 
pycnantha Benth.), a shrub growing in southern 
Australia. Lutz (/. pharm. chim., 1942, 9:2, 49) 
gives Acacia decurrens Willd. var. mollissima 
Willd. as the source of Wattle Gum. However, 
the term "Wattle" is used for any one of various 
species of Acacia of Australia, Tasmania and 
S. Africa which are valued for their gum, bark or 
wood. 

The astringent bark and unripe fruit of the 



Acacia 



Part I 



acacia contain both tannic and gallic acids. The 
dried juice of the pod was used by the ancient 
Greeks; and an extract is still sold in the bazaars 
of India under the name of Akakia. 

The gum of the acacias exudes spontaneously 
from cracks in the bark, and hardens on exposure; 
but in commercial production incisions are usually 
made in order to facilitate the exudation. The 
gum is said also to be found immediately under 
the bark, where it is sometimes collected in 
regular cavities. It is formed within the plant by 
metamorphosis of the cells of the inner bark. 
The tissues involved are chiefly those of the 
sieve and the cambium. The formation of the gum 
is believed to be a pathological process, as gum- 
mosis develops more largely upon the wounding 
of the trees and their infection by bacteria and 
other parasites. The investigations of Smith tend 
to show that all vegetable gums are of bacterial 
origin and that the differences in the several gums 
are due to the differences in the nature of the 
bacteria producing them. (Proc. Linn. Soc. N. S. 
Wales, 1904, p. 217.) For further discussion of 
the origin of acacia gum see Tschirch, "Hand- 
buch der Pharmakognosie," and Greenish, "Mate- 
ria Medica," 4th ed. 

The trees are not tapped for gum until they 
are about six years old. Annual yields from 188 
to 2856 Gm. in young trees and from 379 to 6754 
Gm. in large trees have been reported. The aver- 
age annual yield of gum from young trees is about 
900 Gm. and from old trees over 2 kilos. 

Commercial History and Varieties. — 
There are two principal commercial varieties of 
gum arabic: 1. The Kordofan, Gedaref or Arabian 
Gum, and 2. the Senegal or West African Gum, 
both of these being derived from A. Senegal. The 
former of these has the finer commercial qualities, 
being nearly white or faint yellowish-white and 
yielding a more or less transparent viscid muci- 
lage. 

Kordofan or Arabian Gum. — This is the 
finest variety of gum arabic obtainable. It is 
gathered in the Kordofan province of the Sudan. 
It was formerly the only kind designated as gum 
arabic and entered commerce almost exclusively 
through Egypt. 

It now occurs in two sub-varieties designated 
as "Bleached Kordofan Gum" and "Natural Kor- 
dofan Gum." The bleached variety is the most 
highly esteemed and occurs in white or weak yel- 
low angular fragments or ovoid tears the outer 
surfaces of which bear numerous cracks. The 
natural variety differs from the former by being 
more transparent, owing to fewer cracks, and in 
being more deeply yellow or pinkish in color. 

During the conquest of the Sudan by Anglo- 
Egyptian forces in 1908, a railway was built from 
Egypt to Khartoum in the Sudan, and since ex- 
tended from Khartoum to El Obeid and Gedaref, 
which opened up large areas of acacia country in 
which the gum is now collected. The chief Egyp- 
tian Sudan market is at El Obeid, the shipping 
companies having their main offices at Khartoum 
about 500 miles distant. The finest Egyptian gum 
consists of large roundish or smaller more or less 
irregular fragments, transparent but usually 
rendered opaque upon the surface by innumerable 



minute fissures. For information concerning 
method of collection see U.S.D., 24th ed., p. 2. 
Talca or Talha gum, from A. stenocarpa and 
A. Seyal, is exceedingly brittle, and usually semi- 
pulverulent. It is a mixture of nearly colorless 
and brownish gums, is exported at Alexandria, and 
is sometimes termed gam savakin or Suakin gum. 

Senegal or West African Gum. — This com- 
mercial variety ranks second to the Kordofan 
gum. It is derived front A. Senegal and other 
species of Acacia growing in the Sudan and 
Senegal. It yields a good adhesive mucilage and 
is valuable for technical purposes. Some of the 
best qualities of Senegal gum are also adapted for 
certain pharmaceutical uses. It was introduced 
into Europe by the Dutch. The French afterwards 
planted a colony on the western coast of Africa, 
and took possession of the trade. The dry winds, 
which prevail after the rainy season, cause the 
bark to crack; the juice flows out and hardens in 
masses. It is claimed that the exudation is also 
largely caused by a parasitic plant, Loranthus 
AcacicB Zucc, the gummy exudation freely oozing 
out at the point where the parasite penetrates the 
bark. Senegal gum is usually in roundish or oval 
unbroken tears, or in straight or curled cylindrical 
pieces of various sizes, in the finest grades whitish 
or colorless, but generally yellowish, reddish, or 
brownish-red. The pieces are generally larger than 
those of Kordofan gum, less brittle, fissured, and 
pulverizable, and break with a more conchoidal 
fracture. Vermiform tears are usually present and 
aid in diagnosing this variety. It is shipped from 
the Senegal river to France and the United States. 

The total imports of acacia into this country 
during 1952 were over 20 million pounds, mostly 
from Sudan, Nigeria, East Africa and India. 

Impurities and Adulterations. — As gum 
arabic is usually collected in huge piles at Khar- 
toum, Gedaref, etc., before being shipped to Port 
Sudan the sand and impurities are likely to sift 
to the bottom. As a consequence the first orders 
will be filled with the cleaner article, while the 
latter, containing the siftings, may run as high 
as 4 per cent of ash. The inferior grades are often 
mixed with, or substituted for, the better kinds, 
especially in powder. 

The chief adulterant and substitute for acacia 
within recent years has been Mesquite gum, from 
Prosopis chilensis (Molina) Stuntz (Fam. Legu- 
minosce), a plant indigenous to Mexico. It occurs 
in brownish to reddish-brown tears of variable 
size and differs from acacia in not precipitating 
from its aqueous solution when solutions of ferric 
chloride, lead subacetate or sodium borate are 
added. 

Description. — "Unground Acacia occurs in 
spheroidal tears up to 32 mm. in diameter or in 
angular fragments of white to yellowish white 
color. It is translucent or somewhat opaque from 
the presence of numerous minute fissures; very 
brittle, the fractured surface glassy and occa- 
sionally iridescent. It is almost odorless and has a 
mucilaginous taste. 

"Flake Acacia occurs in white to yellowish 
white, thin flakes, appearing under the microscope 
as colorless, striated fragments. 

"Powdered Acacia is white to yellowish white. 



Part I 



Acacia 



It occurs in angular microscopic fragments with 
but slight traces of starch or vegetable tissues 
present. 

"Granular Acacia is Acacia reduced to fine 
granules. It is white to pale yellowish white. 
Under the microscope it appears as colorless, 
glassy, irregularly angular fragments up to 100 m* 
in thickness, some of which exhibit parallel linear 
streaks. 

"Solubility. — One Gm. of Acacia dissolves in 
2 ml. of water; the resulting solution flows 
readily and is acid to litmus. It is insoluble in 
alcohol." U.S.P. 

Acacia is insoluble in ether, and in oils. In 22 
per cent alcohol the solubility is 57 Gm. in 100 
ml.; in 40 per cent alcohol, 10 Gm. in 100 ml.; 
in 50 per cent alcohol, 4 Gm. in 100 ml. 

Standards and Tests. — Identification. — A 
flocculent, or curdy, white precipitate is produced 
immediately when 0.2 ml. of diluted lead subace- 
tate T.S. is added to 10 ml. of a 1 in 50, cold, 
aqueous solution of acacia. Total ash. — Not over 
4 per cent. Acid-insoluble ash. — Not over 0.5 per 
cent. Water. — Not over 15 per cent. Optical rota- 
tion. — A 1 in 10 solution is only slightly levorota- 
tory. Insoluble residue. — A mixture of 5 Gm. of 
acacia, 100 ml. distilled water and 10 ml. of 
diluted hydrochloric acid boiled gently for 15 
minutes yields a residue not exceeding 50 mg. 
Starch or dextrin. — Iodine T.S. does not give a 
bluish or reddish color with a 1 in 50 aqueous 
solution of acacia, previously boiled and cooled. 
Tannin-bearing gums. — No blackish coloration or 
precipitate is produced when 0.1 ml. of ferric 
chloride T.S. is added to 10 ml. of a 1 in 50 
aqueous solution of acacia. U.S.P. 

The B.P. specifies the following identification 
tests for acacia: (1) A flocculent white precipitate 
is produced on adding a strong solution of lead 
subacetate to a 1 in 50 solution of acacia. (2) 
A deep blue color is produced on adding 0.5 ml. of 
hydrogen peroxide solution and 0.5 ml. of a 1 in 
100 solution of benzidine (in 90 per cent alcohol) 
to a solution of 250 mg. of acacia in 5 ml. of 
water, the mixture being allowed to stand. (3) 
Particles of powdered acacia mounted in solution 
of ruthenium red show no red color when ex- 
amined microscopically (distinction from agar and 
from sterculia). (4) No precipitate is produced on 
adding 0.2 ml. of a 1 in 5 solution of lead acetate 
to 10 ml. of a 1 in 50 solution of acacia (dis- 
tinction from agar and from tragacanth). (5) A 
mixture of 100 mg. of powdered acacia and 1 ml. 
of 0.02 N iodine does not acquire a crimson or 
olive-green color (distinction from agar and from 
tragacanth). 

Gum arabic undergoes no change on aging, if 
kept in a dry place. Its concentrated aqueous 
solution remains stable for a considerable time, 
but ultimately becomes sour, acid being formed. 
The tendency to sour is said to be increased by 
using hot water in making the solution. 

Constituents. — Acacia consists principally of 
the calcium, magnesium and potassium salts of a 
polysaccharide known as arabic acid, sometimes 
called arabin. On hydrolysis with dilute acid, 
arabic acid yields L-arabinose, L-rhamnose, 
D-galactose, and an aldobionic acid containing 



D-glucuronic acid and D-galactose in glycosidal 
combination. An oxidase-type enzyme is present 
in acacia, and it is claimed that diastase is also a 
constituent. 

Incompatibilities. — Bourquelot (/. phartn. 
chim., 1904, 19, 473, 474) reported that acacia 
contains an oxidase-type enzyme which may 
render it unsuitable for use in pharmaceutical 
preparations which contain easily oxidized active 
constituents. Thus, Kedvessy (Chem. Abs., 1943, 
37, 4531) reported that the vitamin A content of 
cod liver oil emulsions made with acacia decreased 
54 per cent in three weeks. Griffiths et al. 
{Analyst, 1933, 58, 65), on the other hand, found 
that such emulsions can be kept for at least four 
months without serious loss of vitamin A if stored 
in well-filled, amber glass bottles and kept in the 
dark. Substances stated to be incompatible with 
acacia include aminopyrine, pyrogallol, morphine, 
vanillin, phenol, thymol, carvol, a- and (5-naphthol, 
pyrocatechol, guaiacol, cresols, creosol, eugenol, 
acetyleugenol, apomorphine, eserine, epinephrine, 
isobarbaloin, caffeotannic acid, gallic acid and 
tannin. Kieft (Pharm. Weekblad, 1939, 76, 1133) 
recommended heating acacia at 103° to 105° C. 
as the best method for destroying its oxidase 
enzyme. The oxidizing action of acacia mucilage 
may be destroyed by heating at 100° C. 

Acacia is also incompatible with strongly alco- 
holic liquids, solutions of ferric chloride and lead 
subacetate, and strong solutions of sodium borate. 

Uses. — Sodium chloride injection is of little 
practical value in the treatment of low blood pres- 
sure from hemorrhage or surgical shock because 
it escapes so rapidly from the blood vessels. This 
characteristic is generally attributed to its non- 
colloid character and in 1917 Bayliss suggested 
the use of a 7 per cent solution of acacia to im- 
part the necessary colloid material. Although the 
method has received some favorable reports (for 
literature see Maytum and Magath, J.A.M.A., 
1932, 99, 2251) the availability of blood plasma 
and plasma expanders, such as dextran and 
polyvinylpyrrolidone, led to an almost complete 
abandonment of the procedure. 

In 1933 Hartmann and co-workers recom- 
mended intravenous injection of acacia solutions 
to relieve the edema of certain types of nephrosis, 
on the theory that the edema is due to a dis- 
turbance of the cclloid pressure of blood brought 
about by a diminution in its protein content. 
There has been considerable difference of opinion 
as to whether the final results are beneficial or 
injurious. Large intravenous doses of acacia in 
animals (15 to 47 Gm. per kilogram in dogs) 
produce toxic effects, including reduction of eryth- 
rocytes, hemoglobin and hematocrit, hastened 
sedimentation of erythrocytes, transitory leuko- 
penia and reduction of serum proteins, especially 
of serum albumin (Hueper, Am. I. Path., 1942, 
18, 895). Tissue examination shows enlargement 
and thickening of the liver. The parenchymal 
cells around the central vein and in the periportal 
areas stain lightly, appear distended and contain 
a vacuolated cytoplasm (foam cells) which does 
not take the special stains used for fat, glycogen, 
mucin or amyloid and is probably acacia. Infiltra- 
tion with inflammatory cells is minimal. The 



Acacia 



Part I 



foam cells persist for 2 years or more and serum 
albumin remains depressed although the level rises 
slowly. Similar foam cells are less numerous in 
the spleen and the convoluted tubules of the 
kidney. 

However, in patients who had received as much 
as 210 Gm. (3.7 Gm. per kilo) of acacia, as long 
as 3 years or as recently as 3 weeks before death 
due to other causes, no such histologic changes 
were observed. Patients given 60 Gm. of acacia 
in the treatment of shock a few days before death 
showed no foam cell changes (Smalley, Binger, 
Bollman and Power, Arch. Int. Med., 1945, 76, 
39). Chemical analyses demonstrate about 20 per 
cent of the acacia in the urine during the first 
few days; some acacia appears in the feces and 
about 20 per cent is stored in the liver; only traces 
are found in other tissues. A decrease in serum 
albumin concentration associated with an increase 
in plasma volume ^ccurs and returns toward 
normal after discontinuing the injections (Yuile 
and Knutti, /. Exp. Med., 1939, 70, 605). A 
variety of tests of liver function reveal no impair- 
ment. In edematous patients, the urinary excre- 
tion of sodium chloride and water is increased. 

Smalley and Binger (J.A.M.A., 1944, 126, 532) 
reported on the condition of patients 2 to 7 years 
after the intravenous injection of acacia. They 
treated 109 patients with the nephrotic syndrome 
in the course of chronic glomerulo-nephritis. 
These edematous patients with hypoproteinemia 
and albuminuria were treated with a low-salt, 
high-protein (75-125 Gm. daily) diet, 1 to 1.5 
liters of fluid daily and 3 Gm. of potassium nitrate 
3 times a day. Edema did not subside in these 
cases. Then, 500 ml. of a 6 per cent solution of 
pure acacia (30 Gm.) in 0.06 per cent sodium 
chloride in distilled water was given intravenously 
on alternate days for 3 doses. After the third in- 
jection the concentration of acacia in the blood 
was about 2 Gm. per 100 ml.; a year later 0.1 Gm. 
per 100 ml. remained. After 2 to 7 years, 12 cases 
were not traced; 72 cases were alive and 49 were 
performing a full day's work, 21 were working 
part-time and 2 were bedfast; the remaining 25 
cases were dead of uremia, hypertension or cardiac 
failure but of these 20 had lost their edema and 
12 had lived 2 years and 5 for 4 years after treat- 
ment with acacia. No evidence of renal or hepatic 
damage was observed in these patients and, in 
fact, many cases showed fewer erythrocytes, leu- 
kocytes and casts in the urine and decreased al- 
buminuria as the edema subsided. In especially 
resistant cases, injection of mercurial diuretics on 
alternate days, between the acacia injections, was 
found to be effective and safe. Most patients 
received 90 Gm. of acacia but, if necessary, as 
much as 200 Gm. appears to be safe. Larger doses 
produce the deleterious effects already described 
(Falkenstein and Jackson, /. Pediatr., 1940, 16, 
700). 

Reactions during injection of acacia occurred 
in 12 of the 109 cases consisting of cold extremi- 
ties, flushing of the face, chill, nausea, vomiting, 
dyspnea and urticaria. Epinephrine effectively 
controlled or prevented these reactions. 

Industrial exposure to acacia, especially as an 
"offset spray" in printing, may cause asthmatic 



seizures. Acacia contains sufficient protein nitro- 
gen to serve as an antigen (Bohner, Sheldon and 
Trenis, /. Allergy, 1941, 12, 290). 

In plastic surgery, a 50 per cent acacia "glue" 
has been employed successfully in grafting de- 
stroyed peripheral nerves (Klemme, Woolsey and 
deRezende, J.A.M.A., 1943, 123, 393). 

In irritations of the mouth or fauces, a small 
lump or lozenge of acacia may be allowed to dis- 
solve slowly in the mouth for its demulcent effect. 
The hygroscopic property of acacia has not proved 
sufficiently marked in the intestine to serve as a 
hydrophilic laxative (Gray and Tainter, Am. J. 
Digest. Dis., 1941,8, 130). 

In pharmacy, acacia is extensively used in the 
preparation of emulsions (see Emulsions, Part II), 
for the suspension of insoluble substances in mix- 
tures, and as a binding agent in tablets, pills and 
troches. For the preparation of emulsions by the 
Continental method, in which acacia is required 
to be mixed with the oil, preference is usually 
given to the finely powdered form; granulated 
acacia, possibly because of its greater content of 
water, dissolves more readily in water with less 
tendency to form lumps and is preferable for the 
preparation of aqueous solutions. As a general 
rule, one part of acacia is sufficient for the emulsi- 
fication of four parts of fixed oil or two parts of 
volatile oil. S 

Off. Prep.— Acacia Mucilage U.S.P., B.P.; 
Cod Liver Oil Emulsion; Liquid Petrolatum 
Emulsion, N.F., B.P.; Compound Chalk Powder; 
Phenolphthalein in Liquid Petrolatum Emulsion, 
N.F.; Compound Powder of Tragacanth, B.P. 

ACACIA MUCILAGE. U.S.P. (B.P.) 

[Mucilago Acaciae] 

B.P. Mucilage of Acacia. Mucilago Gumrai Arabici. 

Fr. Mucilage de gomrae arabique. Gcr. Gummischleim. 

It. Mucillaggine di gomma arabica. Sp. Mucilago de 
goma Arabiga. 

Place 350 Gm. of acacia, in small fragments, 
in a graduated bottle having a wide mouth and a 
capacity not much more than 1000 ml. Wash the 
drug with cold purified water, allow it to drain, 
and add enough warm purified water, in which 2 
Gm. of benzoic acid has been dissolved, to make 
the product measure 1000 ml. Stopper the bottle, 
lay it on its side, rotate it occasionally, and when 
solution has been effected strain the mucilage. 
Acacia mucilage may also be prepared by adding 
400 ml. of purified water, in which the benzoic 
acid has been dissolved with the aid of heat, to 
350 Gm. of powdered or granular acacia and 
triturating until the acacia is dissolved; sufficient 
purified water is added to make the product meas- 
ure 1000 ml. U.S.P. 

"Caution. — Acacia Mucilage must be free from 
mold or any other indication of decomposition." 
U.S.P. 

The B.P. mucilage is prepared by dissolving 
400 Gm. of acacia, previously washed with water, 
in 600 ml. of chloroform water. 

Acacia mucilage does not keep very well. 
Though many suggestions have been offered for 
preserving it, none appears to be entirely satis- 
factory. Generally, addition of a preservative in- 
troduces potential incompatibilities; the use of 



Part I 



Acetanilid 



chloroform water, as directed by the B.P., may be 
objectionable because of the taste it gives to the 
preparation. 

Acacia mucilage is employed as an aid in sus- 
pending insoluble substances in liquids, as an 
emulsifier, and as a pill and tablet excipient. Occa- 
sionally it is employed for its demulcent effect, 
the average dose being 15 ml. (approximately 
4 fluidrachms). 

Storage. — Preserve "in tight containers." 
U.S.P. 

ACACIA SYRUP. U.S.P. 

[Syrupus Acaciae] 

Syrupus Gummi (Gummosus); Sirupus Gummi Arabici. 
Fr. Sirop de gomme. Ger. Gummisirup. It. Sciroppo di 
gomma arabica. Sp. Jarabe de goma. 

Mix 100 Gm. of granulated or powdered acacia, 
1 Gm. of sodium benzoate, and 800 Gm. of 
sucrose; add 425 ml. of purified water, mix, and 
heat the mixture on a water bath until solution 
is effected. Cool, remove the scum, add 5 ml. of 
vanilla tincture and sufficient purified water to 
make the product measure 1000 ml. Strain if 
necessary. U.S.P. 

This demulcent syrup is often effective in mask- 
ing the bitter or acid taste of medicaments, per- 
haps in part functioning by a protective colloid 
action. A dose of 4 to 15 ml. (approximately 1 to 
4 fluidrachms) is used. 

Storage. — Preserve "in tight containers, and 
avoid excessive heat." U.S.P. 



ACETANILID. 

[Acetanilidum] 



N.F. 




NHC0CH 3 



Antifebrin; Phenylacetamide; Acetylamidobenzene; Mono- 
acetylaniline. Fr. Acetanilide. Ger. Azetanilid; Acet- 
phenylamid. Sp. Acetanilida ; Acetilfenilamina. 

Acetanilid, introduced into medicine in 1886 as 
antifebrin, may be prepared by the action of 
acetic anhydride, acetyl chloride, or glacial acetic 
acid on aniline. A commercial process involves 
heating glacial acetic acid and aniline for several 
hours until tests show the absence of unreacted 
aniline. The crude product is purified by re- 
crystallization from hot water. 

Description. — "Acetanilid occurs as white, 
shiny crystals, usually in scales, or as a white, 
crystalline powder. It is odorless, and is stable in 
air. Its saturated solution is neutral to litmus 
paper. One Gm. of Acetanilid dissolves in 190 ml. 
of water, in 3.5 ml. of alcohol, in 4 ml. of chloro- 
form, and in about 17 ml. of ether. One Gm. 
dissolves in 20 ml. of boiling water, and in about 
0.6 ml. of boiling alcohol. It is soluble in glycerin. 
Acetanilid melts between 114° and 116°." N.F. 

Standards and Tests. — Identification. — (1) 
100 mg. of acetanilid boiled with 5 ml. of sodium 
hydroxide T.S. evolves vapors of aniline; addition 
of several drops of chloroform and further heat- 
ing produces phenyl isocyanide, a poisonous com- 
pound recognized by its disagreeable odor. (2) A 
white, crystalline precipitate of ^-bromoacet- 
anilid forms on adding a few drops of bromine 



T.S. to 10 ml. of saturated solution of acetanilid. 
Loss on drying. — Not over 0.5 per cent on drying 
over sulfuric acid for 2 hours. Residue on igni- 
tion. — Not over 0.05 per cent. Readily carboniz- 
able substances. — A solution of 500 mg. of acet- 
anilid in 5 ml. of sulfuric acid has no more color 
than matching fluid A. N.F. 

Incompatibilities. — Acetanilid is incompat- 
ible with alkalies (which liberate aniline) and 
when it is triturated with phenol, resorcinol, 
chloral hydrate, acetylsalicylic acid, antipyrine, 
and many other organic drugs it forms a mixture 
which liquefies. With ethyl nitrite spirit, amyl 
nitrite, or with acid solutions of nitrites a yellow 
solution is produced which turns to red upon 
standing. In acid solutions acetanilid is slowly 
hydrolyzed. Bromides and iodides form with acet- 
anilid a precipitate. Ferric salts produce with it a 
red color. 

Uses. — Acetanilid possesses analgesic and 
antipyretic properties, and is today used in medi- 
cine especially for the former, and to a lesser 
extent for the latter, effect. As with acetophenet- 
idin, it yields in the system principally N-acetyl- 
/»-aminophenol, to which the therapeutic utility 
of the compounds is apparently attributable. 
From 70 to 90 per cent of acetanilid administered 
to humans appears in the urine as conjugation 
derivatives, with sulfuric acid and glucuronic acid, 
of />-aminophenol and its N-acetyl derivative 
(Greenberg and Lester, /. Pharmacol., 1946, 88, 
87). A minor fraction of acetanilid deacetylates 
to aniline (ibid., 1948, 94, 29). 

The most striking actions of acetanilid are upon 
the heat-regulating mechanism and upon pain 
perception. The maintenance of body tempera- 
ture is the result of a delicate balance between 
the amount of heat generated in the system by 
oxidation and that which is utilized or dissipated. 
Antipyretics, including acetanilid, have little if 
any effect on production of heat; their action 
appears to be that of increasing dissipation of heat 
by dilatation of cutaneous blood vessels and by 
increasing the degree of sweating. There is differ- 
ence of opinion as to the advisability of using 
antipyretic drugs to lower body temperature when 
it is elevated. At times these drugs produce such 
a sudden or excessive change as to lead to 
collapse. The need for antipyretic drugs has 
diminished as effective chemotherapeutic agents 
have become available. 

The most important use of acetanilid at the 
present time is for the relief of pain, especially 
that of neuralgia, whether of the head or other 
portions of the body. While it will usually relieve 
even severe neuralgic pains, it is comparatively 
feeble in traumatic conditions. It is believed that 
the analgesic effect is the result of depression of 
the pain-perceiving mechanism. Hale and Grab- 
field (/. Pharmacol., 1923, 21, 77), in experi- 
ments upon men, found that the threshold of 
perception of faradic irritation of the skin was 
raised about 30 per cent. Wolff, Hardy and 
Goodell (/. Clin. Inv., 1941, 20, 62) reported a 
similar degree of reduction in the perception of 
pain caused by radiant heat. The analgesic effect 
appeared about an hour after oral administration, 
and persisted for 2 to 3 hours. Doses larger than 



Acetanilid 



Part I 



300 mg. did not increase or prolong the analgesic 
effect. In the presence of pain induced by a 
tourniquet on the arm which obstructed arterial 
flow for 30 minutes, acetanilid induced the same 
decrease in the sensitivity to the discomfort 
caused by radiant heat on the forehead as it did 
in the absence of pain in the arm. In contrast 
morphine, which raised the threshold about 70 
per cent without pain in the arm, elevated the 
threshold (to heat on the forehead) only about 
30 to 40 per cent when ischemic pain was present 
in the arm. Acetanilid allayed restlessness and 
anxiety more effectively than did 300 mg. of 
acetylsalicylic acid. Combinations with other 
analgesic drugs did not enhance the action above 
that of the most effective component. Mullin and 
Luckhardt (Arch, internal, pharmacodyn. therap., 
1937, 55, 112), on the other hand, did not find 
acetanilid to produce in men any diminution in 
the perception of pressure pain. 

Locally acetanilid is mildly antiseptic and to 
some degree anesthetic. It has been used as a 
dusting powder in various types of ulcers, but its 
use is not free from danger and it does not appear 
to have any great advantage over a number of 
other safer remedies for this purpose. H 

Toxicology. — The freedom with which acet- 
anilid and allied drugs are used by the laity 
makes the subject of their potential danger a 
matter of considerable economic as well as hy- 
gienic importance. Unfortunately, much that has 
been written on the subject has been in the spirit 
of trying to establish a preconceived opinion 
rather than to discover the truth. From the welter 
of polemics, certain deductions are scientifically 
justified. 

In ordinary doses acetanilid has no demonstra- 
ble action on respiration or circulation in lower 
animals, although in very large quantities it acts 
as a depressant to the heart (Higgins and 
McGuigan, /. Pharmacol, 1933, 49, 466). It 
appears also to be feebly depressant to the motor 
centers in the cord. 

Acute poisoning (cyanosis, prostration and col- 
lapse) is rare. The acute lethal dose of acetanilid 
for the lower animals (see Clark, /. Pharmacol., 
1940, 69, 280), and ordinarily for men, is so large 
that one would hardly class it as a poison. On the 
other hand, there have been several deaths from 
acute acetanilid poisoning, one from as little as 
18 grains. Several of these deaths occurred dur- 
ing its use in fever and it is well known that a 
sudden reduction in body temperature may pro- 
duce circulatory collapse. The common custom 
of adding caffeine to acetanilid mixtures to guard 
against cardiac depression has been shown by 
several investigators to be futile; indeed it seems 
well established that caffeine increases the toxicity 
of acetanilid (see Smith and Hambourger. /. 
Pharmacol, 1935. 55, 200 and 1936, 57, 34). The 
number of deaths from acetanilid which can be 
ascribed to idiosyncrasies, compared to the mil- 
lions of doses which have been ingested appears 
singularly small. 

Acute poisoning in children is manifested by 
vomiting, abdominal pain, diarrhea, cyanosis, 
fatigue, vertigo, somnolence, palpitation, muscu- 
lar spasms, delirium and coma. Urticaria is seen. 



Treatment consists of gastric lavage, cathartics, 
an enema, oxygen inhalation and nikethamide, 
pentylenetetrazole, etc. Venesection and replace- 
ment of blood capable of carrying oxygen may be 
necessary. 

It seems definitely established that the con- 
tinued use of acetanilid in large doses (1.5 Gm. 
daily) leads to anemia and degenerative changes 
in the heart and other organs. Chronic poisoning 
is manifested by cyanosis, anorexia, cachexia, 
anemia, varied psychic and neurologic disorders, 
lassitude, insomnia and headache (Lundsteen, 
Meulengracht and Rischel, Acta med. Scandinav., 
1938, 96, 462). Since headache may be the 
symptom for which the drug was taken, a vicious 
cycle is established. Splenomegaly is often asso- 
ciated with the hemolytic anemia. Tolerance to 
large doses may develop and withdrawal symp- 
toms, such as acute mania, have been reported 
(Austin, J.A.M.A., 1942, 120, 911; Mcintosh, 
N. Carolina M. J., 1940, 1, 143; Payne, /. 
Pharmacol, 1935, 53, 401). 

The repeated use of acetanilid in large doses 
leads to a change in the color of the blood. 
Although Young and Wilson (/. Pharmacol, 1926, 
27, 1334) believed that the new pigment is due to 
decomposition products of />ara-aminophenol, the 
observations of Harrop and Waterfield (J. A.M. A., 
1930, 95, 647), of Smith (/. Pharmacol, 1940, 
70, 171) and many others seem to leave no room 
for doubt that there is a formation of either 
methemoglobin, sulfhemoglobin, or both. Bran- 
denburg and Smith (Am. Heart J., 1951, 42, 582) 
reported 62 clinical cases of sulfhemoglobinemia, 
44 of which followed the prolonged ingestion of 
acetanilid alone or in combination with potassium 
bromide and caffeine. Reynolds and. Ware 
(J.A.M.A., 1952, 149, 1538), in reporting 6 cases 
of sulfhemoglobinemia following the prolonged 
use of acetanilid, emphasize that this pigment 
occurs more commonly than methemoglobin. Ac- 
companying the change in hemoglobin there is a 
diminution in the oxygen-carrying power of the 
blood. Methemoglobin is rapidly reversed to 
normal hemoglobin by the enzyme systems in the 
red blood cells as soon as the offending agent is 
removed, but sulfhemoglobin is not reversible to 
hemoglobin and, once formed, it persists for the 
life of the red cell. The two pigments may be 
differentiated by spectroscopic examination of 
the blood. 

Whether acetanilid is to be classed as a habit- 
forming drug depends largely on what one means 
by the term "habit-forming" (whether psychic or 
physical dependence). Undoubtedly, there are 
hundreds of persons who use acetanilid daily, 
just as there are millions who are addicted to caf- 
feine beverages, but we do not believe it is justi- 
fiable to speak of it as a habit-forming drug in the 
sense that opium or alcohol is. despite the report 
of Stewart (J. A.M. A., 1905. 44, 1724). Just how 
much of the drug is needed to bring about these 
noxious effects it is impossible to say. Acetanilid 
is relatively safe as a therapeutic agent but its 
habitual use by the laity is not to be encouraged 
(see also Hanzlik, /. Am. Dent. A., Sept., Oct. 
and Nov., 1940). 

Dose. — The usual dose of acetanilid is 200 mg. 



Part I 



Acetarsone 



(approximately 3 grains), with a range of 200 to 
500 mg. ; not more than 1 Gm. should be taken in 
24 hours. 

Storage. — Preserve "in well-closed con- 
tainers." N.F. 

ACETANILID TABLETS. N.F. 

[Tabellae Acetanilidi] 

"Acetanilid Tablets contain not less than 94 
per cent and not more than 106 per cent of the 
labeled amount of CsHgNO." N.F. 

Assay. — A representative sample of tablets, 
equivalent to about 300 mg. of acetanilid, is 
digested with petroleum benzin to remove lubri- 
cants, after which the acetanilid is extracted with 
chloroform, the solvent evaporated, and the resi- 
due of acetanilid dried at about 80° for 2 hours, 
and finally weighed as CsHgNO. N.F. 

Storage. — Preserve "in well-closed con- 
tainers." N.F. 

Usual Sizes. — 3 and 5 grains (approximately 
200 and 300 mg.). 

ACETARSONE. N.F. (B.P.) LP. 

3-Acetamido-4-hydroxybenzenearsonic 
Acid, [Acetarsonum] 



As0(0H) o 




NHC0CH-, 



"Acetarsone, dried at 105° for 1 hour, yields 
not less than 98.8 per cent and not more than 
101.4 per cent of CsHioAsNOs." N.F. The B.P. 
defines acetarsol as 3-acetamido-4-hydroxyphenyl- 
arsonic acid, and requires it to contain not less 
than 27.1 per cent and not more than 2 7.5 per 
cent of As, calculated with reference to the sub- 
stance dried to constant weight at 105°. The LP. 
limits are 26.8 to 27.5 per cent of As, with refer- 
ence to the substance dried at 100° for 4 hours. 

B.P. Acetarsol. I. P. Acetarsolum. N-acetyl-4-hydroxy-m- 
arsanilic acid. Stovarsol (Merck), Kharophen, Orarsan, 
Spirocid. 

The intermediate from which acetarsone, as 
well as arsphenamine and most other arsenicals, 
may be prepared is 3-nitro-4-hydroxyphenyl- 
arsonic acid (for method of obtaining it see under 
Arsphenamine) . By reducing only the nitro group 
— not the arsenic — in this intermediate and 
acetylating the resulting amino group acetarsone 
is produced. 

Description. — "Acetarsone occurs as a white 
or slightly yellow, odorless powder. It is stable at 
ordinary temperatures. Acetarsone dissolves in 
solutions of alkali hydroxides or carbonates. It is 
slightly soluble in water and insoluble in alcohol. 
Its saturated aqueous solution is acid to litmus 
paper." N.F. The B.P. gives the melting point as 
about 240°, with decomposition. 

Standards and Tests. — Identification. — (1) 
A yellow precipitate is produced on adding 2 Gm. 
of sodium hydrosulfite to a solution of 1 Gm. of 
acetarsone in 10 ml. of sodium hydroxide T.S. 



diluted with 10 ml. of water, the mixture being 
heated in a water bath for 20 minutes; after de- 
canting the supernatant liquid the precipitate dis- 
solves in an excess of sodium hydroxide T.S. (2) 
A yellow precipitate, soluble in ammonium carbo- 
nate T.S., is produced when hydrogen sulfide is 
passed into the solution resulting from the assay 
for arsenic. (3) A solution of 100 mg. of acetar- 
sone in 5 ml. of sodium hydroxide T.S. is evapo- 
rated to about 3 ml., cooled, 2 or 3 drops of 
alcohol and 2 ml. of sulfuric acid added and the 
mixture heated gently : an odor of ethyl acetate is 
apparent. Loss on drying. — Not over 2 per cent, 
when dried at 105° for 1 hour. Residue on igni- 
tion. — Not over 0.2 per cent. Solubility in sodium 
carbonate. — A practically clear solution, not 
darker than a pale yellow, is obtained from 1 Gm. 
of acetarsone and 10 ml. of sodium carbonate 
T.S. Aminohydroxyphenylarsonic acid. — No red 
or brown color is produced on adding 2 drops of a 
1 in 30 potassium dichromate solution to the fil- 
trate obtained by shaking 1 Gm. of acetarsone 
with 10 ml. of a mixture of equal volumes of di- 
luted hydrochloric acid and water and then filter- 
ing. Inorganic arsenates. — No precipitate is pro- 
duced on adding a slight excess of ammonia T.S. 
and 2 ml. of magnesia mixture T.S. to a solution 
of 500 mg. of acetarsone in 10 ml. of water; on 
heating the solution for 10 or 15 minutes a pre- 
cipitate will form. N.F. 

As the test for aminohydroxyphenylarsonic 
acid the B.P. specifies that the color produced 
when a solution of unhydrolyzed acetarsone is 
diazotized and coupled with betanaphthol shall 
not be deeper than that obtained when about 
%ooth of the amount of acetarsone is hydrolyzed 
by acid and similarly diazotized and coupled. 
Loss on drying to constant weight at 105° is 
limited to 0.5 per cent. A limit test for chloride 
is also provided by the B.P. 

Assay. — In the N.F. assay about 200 mg. of 
dried acetarsone is decomposed with potassium 
permanganate and sulfuric acid. Hydrogen per- 
oxide is added to reduce the excess permanganate 
and the pentavalent arsenic is reduced to the 
trivalent state by iodide; the liberated iodine is 
titrated with 0.1 iV sodium thiosulfate. Each ml. 
of 0.1 N sodium thiosulfate represents 13.75 mg. 
of CsHioAsNOs. The B.P. assay provides for 
oxidation of the acetarsone with fuming nitric 
acid and sulfuric acid. The nitric acid is subse- 
quently decomposed with the aid of ammonium 
sulfate, the arsenic reduced by iodide and, finally, 
in the presence of sodium bicarbonate, the tri- 
valent arsenic is oxidized to the pentavalent state 
by titration with 0.1 iV iodine. The LP. assay is 
practically the same as that of the B.P. 

Uses. — This pentavalent arsenical was among 
those which Ehrlich tested but rejected because 
it produced severe nerve disorders in mice. In 
1921 Fourneau introduced it as a preventive and 
curative remedy for syphilis. Its value in this 
condition was studied by Raiziss {Arch. Dermat. 
Syph., 1935, 25, 799) who found that it appar- 
ently penetrates into the spinal canal more easily 
than trivalent arsenicals. While it is apparently 
less efficient than arsphenamine as an antisyphi- 
litic, it is effective when given by mouth. How- 



8 



Acetarsone 



Pari I 



ever, doses which are effective for adult syphilis 
produce toxic effects in from 7 to 20 per cent of 
patients. Because of its toxicity it is generally not 
recommended for the treatment of congenital lues 
in infants (Vem. Dis. Inform., 1942, Suppl. 18, 
1-92). Considering the availability of other and 
safer methods of treating syphilis the risk of 
toxicity from such use of acetarsone is not justi- 
fied. Both acetarsone and its bismuth salt have 
been employed as an adjuvant to the malarial 
therapy of neurosvphilitic insanitv (Parkenham- 
Walsh. J. Meat. Sc, 1942. 88, 344). 

Yaws has been successfully and cheaply treated 
with oral doses of 250 mg. daily in 3 courses of 
20 days each, separated by 14-day intervals with- 
out medication (Pardo-Costello, Arch. Dermat. 
Syph., 1939. 40, 762). 

Vincent's angina responds favorably to 250 mg. 
of acetarsone in a paste made with glycerin or 
water and locally applied (Maxwell. Pract., 1936. 
2, 660). In a jelly vehicle it has given prompt 
relief in fusospirochetal balanitis (Thompson. 
Brit. M. J., 1943. 2, 485). Meigs (New Eng. J. 
Med., 1942. 226, 562) and others have used 
acetarsone with success in trichomonas vaginitis; 
100 mg. may be applied as a powder or in aqueous 
solution in the office, and a tablet or impregnated 
tampon containing acetarsone, with glucose, lactic 
and boric acids, starch, sodium bicarbonate and 
tartaric acid prescribed for insertion at bedtime. 
A powder containing 12.5 per cent of acetarsone 
with kaolin and sodium bicarbonate is used by 
some physicians for insufflation every second or 
third day until three or four treatments have been 
given. 

In amebic dysentery Faust. D'Antoni and 
Sawitz {Clin. Med., 1943. 50, 261) found acet- 
arsone highly effective; they administered 260 
mg. twice a day for two days, then three times 
daily for three days. Balantidiasis also responds 
to this drug (McCarey. Brit. M. J., 1952, 1, 629). 
Acetarsone is reported to be valuable in the 
treatment of pemphigus (Oppenheim and Cohen, 
Arch. Dermat. Syph., 1950. 61, 500); and of 
diphtheria carriers, being administered by nasal 
instillation (Brit. M. J., 1937. 1, 2). 

Acetarsone is completely absorbed, after oral 
administration, and rapidly excreted in the urine, 
with only small amounts stored in the fiver and 
other tissues (Dimter and Allin. Ztschr. Ki?idcrh., 
1943. 63, 760). It should be remembered that 
although acetarsone is generally given by mouth 
it is capable of giving rise to the same group of 
toxic manifestations that follow arsphenamine. 
The effective dose nearly equals the toxic dose. 
Toxic effects are infrequent if rest periods of 
three to five days are prescribed between each 
three to five days of administration. Deaths have 
been due to nephritis, neuritis, encephalitis, ex- 
foliative and bullous dermatitis, hepatitis, aplastic 
anemia and indefinite causes. Less severe reac- 
tions include erythema, diarrhea, vomiting, fever, 
albuminuria, paresthesias and vertigo. Acetarsone 
is contraindicated in patients with disease of the 
cardiovascular system, impaired liver or kidney 
function, optic neuritis, fever or recent hemor- 
rhage (Ven. Dis. Inform., 1942, Suppl. 18, 1-92). ® 



Dose. — The range is from 60 to 250 mg. (ap- 
proximately 1 to 4 grains), two or three times a 
day. It should not be continued for more than a 
week or 10 days; treatment may be resumed after 
a rest period. 

Derivatives. — A water-soluble sodium deriva- 
tive of acetarsone. suitable for the preparation of 
injections, is sold abroad. Other derivatives are 
the bismuth compound, generally injected as an 
oil suspension, and the water-soluble diethyla- 
mine acetarsol, known as Acetylarsan (Merck), 
used intramuscularly or subcutaneously. 

Storage. — Preserve "in well-closed contain- 



ers." X.F. 



ACETARSONE TABLETS. 

[Tabellae Acetarsoni] 



X.F. 



'Acetarsone Tablets contain not less than 92.5 
per cent and not more than 107.5 per cent of the 
labeled amount of CvHu.AsXO-,." X.F. 

Usual Sizes.— 10, 50, 100, and 250 mg. (ap- 
proximately %, H, 1%, and 4 grains). 

ACETIC ACID. U.S.P., B.P. 

[Acidum Aceticum] 

"Acetic Acid is a solution containing not less 
than 36 per cent and not more than 37 per cent, 
by weight, of C2H4O2." U.S.P. The B.P. requires 
33.0 per cent w/w of C2H4O2 (limits, 32.5 to 

OO.J). 

Ethanoic Acid. Acetum Concentratum : Acidum Aceticum 
Dilutum (.Get., Sp.) Ger. Verdiinnte Essigsaure. Sp. Acido 
acetico diluido. 

Formerly the chief commercial source of acetic 
acid was the destructive distillation of wood. 
When carbonized out of contact with air. wood 
yields many volatile products, among which are 
an acid liquor called pyroligneons acid, an empy- 
reumatic oil. and tar containing creosote and some 
other proximate principles (see Pine Tar). When 
the carbonization is performed in closed vessels. 
these products may be collected, and, at the same 
time, a large amount of charcoal be obtained. In 
the case of resinous woods, wood oil and turpen- 
tine oil are obtained before the charring tempera- 
ture is reached. 

Crude pyroligneous acid, sometimes called 
pyroligneons vinegar, or wood vinegar, is a dark 
brown liquid, having a strong smoky odor, and 
consisting of acetic acid, methanol, acetone, water 
and more or less tar. At one time the crude 
pyroligneous acid was converted to calcium ace- 
tate by treatment with lime, and the acetic acid 
obtained by subsequent distillation with sulfuric 
acid. This method of recovering acetic acid from 
pyroligneous acid is no longer economically prac- 
ticable; at present, the acetic acid is separated 
by processes invoking solvent extraction, as with 
isopropyl ether, and removal of water by azeo- 
tropic distillation, using a water-entraining liquid 
(see Glacial Acetic Acid). The product can readily 
be concentrated, if desired, to contain over 99 per 
cent of CH3COOH. 

During the first World War the facilities of 
the wood distillation industry were found to be 



Part I 



Acetic Acid 



entirely inadequate to supply the demand for 
acetic acid and it was made from molasses which 
had been fermented into alcohol. In this process 
conversion of the molasses alcohol into acetic acid 
was accomplished by the quick fermentation proc- 
ess in which weak alcohol was passed through 
percolators filled with beech wood shavings which 
had been inoculated with Mycoderma aceti. An- 
other method for the rapid production of acetic 
acid, introduced during the same war, depends on 
the conversion of acetylene to acetaldehyde which 
is then readily oxidized to acetic acid by means 
of air; catalysts are employed in both reactions. 

Still another process for the manufacture of 
acetic acid is the oxidation of alcohol vapor by 
air in the presence of suitable catalysts. Acetic 
acid may also be produced by heating a mixture 
of carbon monoxide and methyl alcohol in the 
presence of catalysts. 

Description. — "Acetic Acid is a clear, color- 
less liquid, having a strong, characteristic odor, 
and a sharply acid taste. Acetic Acid is miscible 
with water, with alcohol, and with glycerin. The 
specific gravity of acetic acid is about 1.045." 
U.S.P. 

The specific gravity of acetic acid increases 
with concentration to a maximum of 1.0681 at 
25° C. (76-79 per cent HC2H3O2), after which it 
decreases until it reaches 1.0471 at 25° C, the 
specific gravity of the 100 per cent acid. The 
specific gravities of the glacial (100 per cent) and 
the 39 per cent acid are practically the same, and 
this applies also to the 74 and 81 per cent acids. 

Standards and Tests. — Identification. — 
Acetic acid responds to tests for acetate. Non- 
volatile residue. — Not over 1 mg. of residue re- 
mains when 20 ml. of acetic acid is evaporated on 
a water bath and dried at 105° for 1 hour. 
Chloride. — No opalescence is produced when silver 
nitrate T.S. is added to a 1 in 10 aqueous solution 
of acetic acid. Sulfate. — No turbidity is produced 
when barium chloride T.S. is added to a 1 in 10 
aqueous solution of acetic acid. Heavy metals. — 
The limit is 10 parts per million. Readily oxidiz- 
able substances. — The color of 4 ml. of acetic 
acid, 20 ml. of distilled water, and 0.3 ml. of 
0.1 N potassium permanganate does not change 
to brown at once nor does it lose its pink tint en- 
tirely in less than 30 seconds. U.S.P. 

The B.P. specifies a test for limit of formic 
acid and of oxidizable impurities in which the 
acid is mixed with 0.1 N potassium dichromate 
and sulfuric acid and, after standing for a minute, 
with a solution of potassium iodide; a yellow or 
brown color should be produced immediately, in- 
dicating the presence of less than the limit of 
impurity. An arsenic limit of 2 parts per million 
and a lead limit of 1 part per million are stipu- 
lated. Other tests are similar to corresponding 
tests in the U.S.P. 

Assay. — A sample of about 6 ml. is weighed, 
diluted with water, and titrated with 1 N sodium 
hydroxide, using phenolphthalein indicator. Each 
ml. of I N sodium hydroxide represents 60.05 mg. 
of C2H4O2. U.S.P. 

Uses. — Acetic acid has an active astringent ac- 
tion and is occasionally used for this purpose in 



skin diseases; it is also employed as a styptic. 
Along with copious amounts of water, a 3 per 
cent or less concentrated solution of acetic acid 
may be used to neutralize alkali burns of the skin; 
the heat produced in the neutralization of residual 
alkali may aggravate the injury if the acid is con- 
centrated. A 0.5 per cent solution is used as a 
cleansing agent or for moistening compresses on 
infected burns or other wounds of the skin; this 
concentration is bacteriostatic for most common 
bacteria. Nielson (J. A.M. A., 1934, 102, 1179) 
recommended 18 per cent acetic acid as a local 
application, every third or fourth day, in the 
treatment of various forms of ringworm of the 
skin, such as tinea capitis and athlete's foot. A 
1 per cent solution is an effective surgical dress- 
ing for pyocyaneus infections. Boiled household 
vinegar, equivalent to 5 per cent acetic acid, was 
instilled into the external auditory canal in cases 
with purulent drainage from chronic otitis media 
by Ochs (Arch. Otolaryng., 1950, 52, 935); when 
the canal was thoroughly cleansed, a tampon of 
cotton was inserted against the drum, moistened 
with the vinegar and left for 2 days. Infection 
cleared after 1 to 3 treatments in 36 ears and 
relapsed in only 5. In chronic pulmonary suppura- 
tion due in part at least to Pseudomonas aeru- 
ginosa, Currence (Am. J. Dis. Child., 1952, 83, 
637) used 1 ml. of a 1 : 1000 solution as an aerosol 
three times daily; symptoms were relieved al- 
though the bacteria persisted. Steam inhalations 
from 30 ml. of vinegar in a liter of water were 
also used. For urinary infections with cystitis an 
0.5 to 1 per cent solution is used as a bladder 
irrigation, especially for ammonia-forming bac- 
teria. As an acid (pH 5) vaginal douche, 1 to 2 
per cent acetic acid (%. to x /z cup of white vine- 
gar to 2 quarts of warm water) is commonly 
used (Hirst, Am. J. Obst. Gynec, 1952, 64), in 
the treatment of Trichomonas vaginalis and other 
types of vaginitis. For contraceptic purposes, 1 
per cent acetic acid has been incorporated in a 
mucilaginous vehicle containing tragacanth, acacia, 
agar, etc. 

Internally, acetic acid is occasionally employed 
as a refrigerant drink, but it is less palatable than 
citric acid solution. Because it is completely 
oxidized in the body acetic acid does not affect 
the acidity of the general system. As an emer- 
gency remedy in hemorrhage from the stomach, 
diluted acetic acid, mixed with an equal volume 
of water — so that the solution contains about 
3 per cent of HC2H3O2 — has been used in table- 
spoonful doses every few minutes as required. Be- 
cause of its volatility and pungency, the vapor of 
acetic acid is used for inhalation in the treatment 
of faintness and sick headache, in the same man- 
ner as smelling salts. This action, like that of 
ammonia, is due to reflexes from irritation of the 
mucous membrane of the nose. The N.F.V. recog- 
nized, under the name Acetum Aromaticum, a 
mixture containing several volatile oils, with 
acetic acid, for this particular use. 

Acetic acid possesses extraordinary solvent 
power for many organic substances, and enhances 
the miscibility of many, otherwise immiscible, 
liquids with water. Charles F. Squibb and J. P. 



10 



Acetic Acid 



Part I 



Remington called attention to the solubilizing 
effect of acetic acid when used in the menstrua 
for extracting certain drugs, and proposed a class 
of preparations, called acetracts, as substitutes for 
the conventionally prepared solid extracts. |v] 

Dose, 0.3 to 0.6 ml. (approximately 5 to 10 
minims), diluted with water; topically, 0.5 to 20 
per cent solutions are used. 

Storage. — Preserve "in tight containers." 
U.S.P. 

Off. Prep.— Diluted Acetic Acid, N.F., B.P.; 
Aluminum Subacetate Solution, U.S. P.; Lobelia 
Tincture, N.F. 

GLACIAL ACETIC ACID. U.S.P., B.P. 

[Acidum Aceticum Glaciate] 
CH3.COOH 

"Glacial Acetic Acid contains not less than 99.4 
per cent, by weight, of C2H4O2." U.S.P. The B.P. 
rubric is not less than 99.0 per cent C2EUO2. 

Crystallizable Acetic Acid. Acidum Aceticum Concen- 
tratum; Acidum Aceticum {Fr., Ger., It., Sp.). Fr. Acide 
acetique; Acide acetique cristallisable; Acide acetique pur. 
Ger. Essigsaure; Eisessig. It. Acido acetico. Sp. Acido 
acetico; Acido Acetico Glacial; Acido etanoico. 

Formerly glacial acetic acid was prepared by 
distilling a mixture of anhydrous sodium acetate 
and sulfuric acid, but it is now prepared by con- 
centrating weaker solutions of acetic acid. Com- 
mercial processes depend upon the separation of 
water by fractional distillation, by formation of 
compounds with anhydrous salts, by refrigeration, 
by entrainment with an organic solvent or by 
other chemical reactions. Thus, acetic acid may 
be rendered anhydrous by rectification with dieth- 
ylcarbonate which lowers the boiling point of 
the water. By this means 50 per cent acetic acid 
may be distilled to produce an acetic acid of 99.8 
to 100 per cent purity. In another process acetic 
acid is dehydrated by treating it with a water- 
entraining liquid such as ethylene or propylene 
chloride which, together with the entrained water, 
is subsequently separated from the acetic acid by 
distillation. 

Description. — "Glacial Acetic Acid is a color- 
less, clear liquid, having a pungent, characteristic 
odor, and, when well diluted with water, an acid 
taste. It boils at about 118° and has a specific 
gravity of about 1.049. Glacial Acetic Acid is 
miscible with water, with alcohol, and with glyc- 
erin. Glacial Acetic Acid congeals at a tempera- 
ture not lower than 15.6°." U.S.P. The B.P. states 
that glacial acetic acid crystallizes at about 10° 
and does not completely remelt until warmed to 
about 15°. The freezing point is given as not lower 
than 14.8°. 

Standards and Tests. — Identification. — Tests 
for acetate are given by a mixture of 1 volume of 
glacial acetic acid and 2 volumes of water. Non- 
volatile residue. — Not over 1 mg. of residue re- 
mains when 20 ml. of glacial acetic acid is evapo- 
rated in a tared porcelain dish and dried at 105° 
for 1 hour. Chloride. — Silver nitrate T.S. pro- 
duces no opalescence when added to a 1 in 20 
aqueous solution of glacial acetic acid. Sulfate. — 
Barium chloride T.S. produces no turbidity when 



added to a 1 in 10 aqueous solution of glacial 
acetic acid. Heavy metals. — The limit is 10 parts 
per million. Readily oxidizable substances. — The 
pink color of a mixture of 2 ml. of glacial acetic 
acid, 10 ml. of water, and 0.1 ml. of 0.1 N potas- 
sium permanganate is not changed to brown within 
2 hours. U.S.P. 

The tests described in the B.P. are similar to 
those described under Acetic Acid, exceptions 
being the arsenic limit of 6 parts per million and 
the lead limit of 3 parts per million. 

Assay. — A sample of about 2 ml. of acid is 
weighed in a glass-stoppered flask, diluted with 
distilled water, and titrated with 1 N sodium hy- 
droxide, using phenolphthalein T.S. as indicator. 
Each ml. of 1 N sodium hydroxide is equivalent 
to 60.05 mg. of C2H4O2. U.S.P. 

Uses. — Glacial acetic acid is comparatively 
little employed as a therapeutic agent; it is official 
chiefly because it is an ingredient of other official 
preparations. It was formerly used to some extent 
as a caustic for the removal of warts and corns, 
but has been largely replaced by the more efficient 
trichloroacetic acid or the high-frequency electric 
current. When properly diluted, it may, of course, 
be employed for the various purposes described 
under Acetic Acid, (v] 

Glacial acetic acid possesses the property of 
dissolving a number of substances, such as volatile 
and fixed oils, camphor, resins, gelatin, etc. It 
also promotes the mutual solubility of partially 
miscible liquids. As it attracts moisture from the 
atmosphere, it should be preserved in well-stop- 
pered bottles. 

Toxicology. — The ingestion of glacial acetic 
acid is followed by severe pain in the mouth, 
throat and abdomen. White plaques and ulcers 
are seen on the mucous membranes. Vomiting and 
hematemesis occur and diarrhea may follow. 
Hoarseness, rapid and shallow respiration, and 
circulatory collapse appear. Body temperature is 
subnormal. Albuminuria, oliguria and uremia may 
develop. 

Morphine injection is indicated for pain. Gas- 
tric lavage or bicarbonate salts are contraindicated 
since they may rupture the eroded stomach. A 
suspension of 60 Gm. of calcium or magnesium 
hydroxide in 500 ml. of water should be ingested 
if possible. Milk, egg white and other demulcent 
substances are indicated. Parenteral fluids and 
supportive measures are important. 

Chronic poisoning causes pallor, cachexia, ero- 
sion of the teeth, halitosis, bronchitis and gastro- 
intestinal disturbances. Industrial exposure to the 
vapors results in conjunctivitis and blepharitis. 

Storage. — Preserve "in tight containers." 
U.S.P. 

Off. Prep. — Aluminum Acetate Solution, 
U.S. P.; Cantharides Tincture, N.F.; Strong Solu- 
tion of Ammonium Acetate, B.P. 



DILUTED ACETIC ACID. N.F. (B.P.) 

[Acidum Aceticum Dilutum] 

"Diluted Acetic Acid is a solution containing, 
in each 100 ml., not less than 5.7 Gm. and not 
more than 6.3 Gm. of C2H4O2." N.F. 



Part I 



Acetone 



11 



Diluted acetic acid may be prepared by mixing 
158 ml. of acetic acid with sufficient purified 
water to make 1000 ml. N.F. 

The B.P. formula yields a preparation of the 
same strength. 

B.P. Dilute Acetic Acid. Fr. Acide acetique dilue ; 
Solution aqueuse, au dixieme, d'acide acetique. 

Description. — "Diluted Acetic Acid is a clear, 
colorless liquid having a characteristic odor, and 
a sharply acid taste. Diluted Acetic Acid is 
miscible with water, with alcohol and with glyc- 
erin. Its specific gravity is about 1.008." N.F. 

For therapeutic uses of this substance, see under 
Acetic Acid. 

Storage. — Preserve "in tight containers." N.F. 

Off. Prep. — Ammonium Acetate Solution; 
Iron and Ammonium Acetate Solution; Squill 
Vinegar, N.F.; Tincture of Ipecac, B.P. 



ACETOMENAPHTHONE. 

Acetomenaphthonum 



B.P. 



The B.P. defines Acetomenaphthone as 1 :4- 
diacetoxy-2-methylnaphthalene and requires not 
less than 98.0 per cent of C15H14O4, referred to 
the substance dried to constant weight at 80°. 

Menadiol Diacetate. 2-Methyl-l,4-naphthohydroquinone 
Diacetate. 

The B.P. states that acetomenaphthone may be 
prepared by reducing 2-methyl-l,4-naphthoquinone 
(menadione) with zinc and acetic acid in the pres- 
ence of acetic anhydride. The compound thus 
represents menadione which has been reduced to 
its corresponding hydroquinone and the two 
hydroxyl groups of the latter acetylated. In the 
B.P. synthesis nascent hydrogen produced by the 
interaction of zinc and acetic acid effects the re- 
duction, while the acetic anhydride accomplishes 
the acetylation. The synthesis of acetomenaph- 
thone has also been described by Anderson and 
Newman (/. Biol. Chem., 1933, 103, 405), who 
prepared it as an intermediate in the synthesis of 
the tubercle bacillus pigment phthiocol, which is 
2-methyl-3-hydroxy- 1 ,4-naphthoquinone. 

Description and Standards. — Acetomenaph- 
thone is a white, crystalline powder, odorless or 
with a slight odor of acetic acid. It is almost in- 
soluble in water, slightly soluble in cold alcohol, 
soluble in 3.3 parts of boiling alcohol. 

It may be identified by a test in which the 
compound is hydrolyzed with sodium hydroxide, 
and the resulting hydroquinone oxidized with 
hydrogen peroxide to menadione; tests are then 
applied for both acetate and menadione. 

The melting point of acetomenaphthone is be- 
tween 112° and 115°. The absorbancy of a 0.003 
per cent w/v solution in dehydrated alcohol, at 
285 m\i, is between 0.69 and 0.78. One Gm. con- 
tains no more zinc than corresponds to 0.2 mg. of 
zinc sulfate. When dried to constant weight at 80° 
the loss in weight is not over 1.0 per cent. The 
limit of sulfated ash is 0.1 per cent. 

Assay. — A sample of about 200 mg. of aceto- 
menaphthone is boiled with a mixture of 15 ml. 
of glacial acetic acid and 15 ml. of diluted hydro- 
chloric acid, under a reflux condenser, for 15 
minutes to remove the acetate groups by hydrol- 



ysis; the resulting hydroquinone is quantitatively 
oxidized to quinone by titration with 0.05 N eerie 
ammonium sulfate, using o-phenanthroline-ferrous 
complex as indicator. A second titration is per- 
formed in the same manner, except that the 
sample is omitted and that the solution is not 
heated; this corrects for any reducing substances 
in the reagents. Each ml. of the difference in the 
volumes of eerie ammonium sulfate solution re- 
quired represents 6.457 mg. of C15H14O4; this 
equivalent is based on two eerie ions being re- 
quired to oxidize the hydroquinone derived from 
acetomenaphthone. B.P. 

Uses. — Acetomenaphthone is intended for oral 
administration in the treatment or prevention of 
vitamin K deficiency and the hypoprothrombinemia 
resulting therefrom. Its relationship to menadione 
has been referred to above; it differs from 
menadiol sodium diphosphate (q.v.) in being a 
diacetate of menadiol instead of the tetrasodium 
salt of the diphosphate of menadiol. 

Ansbacher and colleagues (J.A.C.S., 1939, 61, 
1924; 1940, 62, 155) observed that several de- 
rivatives of 2 -methyl- 1,4-naphthohydroquinone 
(referred to as menadiol) exert, in lower animals, 
the typical effect of the K vitamers in restoring 
coagulability of the blood in animals suffering 
from vitamin K deficiency. They found that 
menadiol diacetate (acetomenaphthone) had to 
be given in about twice the dose of menadione to 
produce the same degree of therapeutic effect. 
Fieser et al. (J. Biol. Chem., 1941, 137, 680) 
estimated the antihemorrhagic potency of aceto- 
menaphthone to be about one-third that of 
menadione. Since the toxic dose of acetomenaph- 
thone is more than three times as large as that 
of menadione (Ansbacher et al., J. Pharmacol., 
1942, 75, 111), the ratio of efficacy to toxicity 
is better for acetomenaphthone than for mena- 
dione. Ewing et al. (J. Biol. Chem., 1939, 131, 
345) called attention to a further advantage of 
acetomenaphthone in not being adversely affected 
by light, as is the case with menadione. 

Fantl et al. (Australian J. Exp. Bio. Med. Sc, 
1951, 29, 433) found that the presence of bile in 
the intestine is not essential for enteric absorption 
of acetomenaphthone; they proposed a test of 
vitamin K deficiency based on urinary excretion 
of the drug following an oral dose of 50 to 60 mg., 
the excretion in the normal individual exceeding 
15 per cent of the ingested dose in 24 hours. 
Douglas and Brown (Brit. M. J., 1952, 1, 412) 
found acetomenaphthone to be less effective than 
vitamin Ki (phytonadione) in correcting the 
hypoprothrombinemia induced by Tromexan. 

The dose of acetomenaphthone is 2 to 10 mg. 
(approximately 1/30 to 1/6 grain) by mouth daily. 

The B.P. recognizes Tablets of Acetomenaph- 
thone, requiring not less than 92.5 per cent and 
not more than 107.5 per cent of the labeled 
amount of C15H14O4. 

ACETONE. N.F. 

Dimethyl Ketone, [Acetonum] 
CH3.CO.CH3 

"Acetone contains not less than 99 per cent of 
CaHeO." N.F. 



12 



Acetone 



Part I 



Dimethylketone; Diraethylketal; Propanone; Pyroacetic 
Ether. Fr. Acetone. Ger. Azeton ; Essiggeist; Mesitalkohol. 
Sp. Acetona. 

Acetone is found in small amount in normal 
urine, in blood, etc., and in larger amount in cer- 
tain pathological conditions. It is a product of the 
dry distillation of sugar, gum, cellulose, etc. 

Acetone may be made in commercial quan- 
tities by the dry distillation of calcium acetate at 
a temperature not exceeding 300°. The crude 
acetone thus obtained may be purified by digestion 
with quicklime and again distilled from sodium 
hydroxide. During the first World War the large 
demand for acetone led to the development of a 
process in which corn starch was fermented by 
Clostridium acetobutylicum Weizmann. yielding 
butyl alcohol, acetone, and ethyl alcohol. Later a 
process was developed in which the Bacillus aceto- 
ethylicitm was employed; this resulted in the 
formation of acetone and ethyl alcohol. Today 
both processes, in many different modifications, 
are in use; the raw materials include a wide 
variety of carbohydrates, especially molasses, but 
including also potatoes, Jerusalem artichokes and 
plant wastes rich in pentosans (corn stalks, wheat 
and rye bran, etc.) ; for a review of the recent 
production status see hid. Eng. Cliem., 1952, 44, 
1677. Acetone has also been produced commer- 
cially starting with propylene made from petro- 
leum, and it can be prepared catalytically from 
ethanol. 

Description. — "Acetone is a transparent, 
colorless, mobile, volatile liquid, having a char- 
acteristic odor. A solution of Acetone (1 in 2) is 
neutral to litmus. Acetone is miscible with water, 
with alcohol, with ether, with chloroform, and 
with most volatile oils. The specific gravity of 
Acetone is not more than 0.789, indicating not 
less than 99 per cent of C3H6O. Acetone distils 
between 55.5° and 57°." 

Standards and Tests. — Identification. — (1) 
A yellow precipitate of iodoform is obtained on 
adding a few ml. of iodine T.S. to a warm mixture 
of 1 ml. of sodium hydroxide T.S. and 1 ml. of a 
1 in 200 aqueous solution of acetone. (2) A deep 
red color is produced when 1 ml. of a 1 in 200 
aqueous solution of acetone is mixed with 5 drops 
of sodium nitroprusside T.S. and 2 ml. of sodium 
hydroxide T.S., then acidified slightly with acetic 
acid; on diluting the mixture with several volumes 
of distilled water a violet tint develops. Non- 
volatile residue. — Not over 2 mg. from 50 ml. of 
acetone, evaporated in a tared porcelain dish on a 
water bath and dried at 105° for 1 hour. Readily 
oxidizable substances. — A mixture of 20 ml. of 
acetone and 0.1 ml. of 0.1 N potassium per- 
manganate is not decolorized within 15 minutes. 
N.F. 

Distilled with water and chlorinated lime, ace- 
tone yields nearly twice its weight of chloroform, 
and hence is largely used to produce the latter. 

Uses. — Acetone is used chiefly as a solvent, 
especially for fats, resins, camphors, and pyroxy- 
lin; it was employed as a menstruum for ex- 
tracting oleoresins in U.S. P. VIII. It is sometimes 
included in the formulation of topically applied 
antiseptic solutions to facilitate penetration and 



intimate contact with the skin, and to hasten 
evaporation of the solvent following application 
of the solution. Some physicians use it in prefer- 
ence to ethyl alcohol for cleansing the skin in 
preparation for smallpox vaccination. Prolonged 
or repeated contact of acetone with the skin causes 
erythema and dryness. Acetone is used as the de- 
naturing ingredient in some formulas for denatured 
alcohol. 

In a general way, the physiological effects of 
acetone seem to resemble those of alcohol. The 
metabolism of acetone was reported by Price and 
Rittenberg (/. Biol. Chem., 1950. 185, 449 j; the 
fate of acetone labeled with the radioactive isotope 
C 14 was reported by Sakami and Lafaye {ibid., 
1951, 193, 199). Koehler et al. (ibid., 1941, 140, 
811) gave intravenous injections of acetone at 
the rate of 5 Gm. per hour to human subjects 
without any symptomatic effects other than slight 
drowsiness. The rate of acetone breakdown as 
judged from blood levels and urinary excretion 
was extremely slow. Data on respiratory excretion 
of acetone were reported by Henderson et al. 
(Diabetes, 1952, 1, 188). 

A liver function test employing an intravenous 
injection of 40 ml. of a 5 per cent solution of 
acetone containing 1 Gm. of sodium bicarbonate, 
followed by a determination of the blood acetone 
level after 12 hours, was described by Schumann 
and Klotzbucher (Klin. Wcknschr., 1940, 19, 
1101). 

The industrial hazard to health from exposure 
to acetone has been studied by Haggard et al. 
(J. Indust. Hyg. Toxicol., 1944, 26, 133). In- 
halation of vapors of acetone will cause headache, 
excitement, and fatigue; at high concentrations 
unconsciousness and narcosis mav result (Chatter- 
ton and Elliot. J. A.M. A., 1946, 'l30, 1222). The 
patient should have access to fresh air, and oxygen 
inhalation and stimulants should be employed if 
required. Albertoni found that doses of 15 to 20 
Gm. of acetone produced no symptoms in man 
beyond slight narcosis. 

Storage. — Preserve "in tight containers, re- 
mote from fire." N.F. 

Off. Prep. — Surgical Merbromin Solution; 
Xitromersol Tincture; Thimerosal Tincture, N.F. 

ACETOPHENETIDIN. U.S.P. (B.P., LP.) 

Acetphenetidin, Phenacetin, [Acetophenetidinum] 



C 2 H 5 




NH-C0-CH 3 



The B.P. defines Phenacetin as aceto-/>-phenet- 
idide, while the LP. defines it as aceto-4-phenet- 
idine. 

B.P., LP. Phenacetin, Phenacetinum. Para-acetphenet- 
idine; Para-acetaminophenetol. Acetphenetidinum ; Ethoxy- 
para-acetanilidum; Acethylphenetidina; Acethylphenet- 
idinum. Fr. Ethoxypara-acetanilide ; Phenedine; Phenine. 
Ger. Phenazetin. It. Acetilfenetidina. Sp. Acetilfeneti- 
dina ; Acetofenetidina; Fenedina; Fenina; Fenacetina. 

Acetophenetidin may be manufactured by any 
one of several processes, the choice of the method 
depending on the availability of the respective 
starting materials and the economy of their utili- 



Part I 



Acetophenetidin Tablets 13 



zation. In one process phenol is converted to a 
mixture of ortho- and />ara-nitrophenol ; the 
former, which is not utilizable, is removed by dis- 
tillation with steam. The sodium derivative of 
the />ara-nitrophenol is treated with ethyl chloride 
or ethyl bromide, producing ethyl />-nitrophenol 
or p-nitrophenetol, C6H4(N02jOC2H5. This is 
reduced with sodium sulfide or with iron filings 
and hydrochloric acid to p-phenetidin, CeHU- 
(NH2)OC2Ho. Glacial acetic acid or any other 
acetylating agent is used to introduce the acetyl 
group, producing />-acetophenetidin. Monochloro- 
benzene, normally less costly than phenol, may 
also be employed as the starting point for the 
synthesis of acetophenetidin; by nitration £-chlo- 
ronitrobenzene is obtained and this, by treatment 
with alkali, is converted to p-nitrophenol which is 
treated as described above. Acetophenetidin may 
also be prepared from />-acetaminophenol by 
ethylation. In still another method acetophenet- 
idin is obtained by the action of the gas ketene, 
CH2=CO, on />-phenetidin dissolved in acetone 
or other inert solvent. 

Description. — "Acetophenetidin occurs as 
white, glistening crystals, usually in scales, or as 
a fine, white, crystalline powder. It is odorless, 
has a slightly bitter taste, and is stable in air. Its 
saturated solution is neutral to litmus. One Gm. 
of Acetophenetidin dissolves in about 1300 ml. of 
water, in 15 ml. of alcohol, in 15 ml. of chloro- 
form, and in about 130 ml. of ether. One Gm. of 
Acetophenetidin dissolves in 85 ml. of boiling 
water, and in about 3 ml. of boiling alcohol. 
Acetophenetidin melts between 134° and 136°." 
U.S.P. 

Standards and Tests. — Identification. — A 
ruby red color slowly develops when 200 mg. 
acetophenetidin is boiled for 1 minute with 1 ml. 
of hydrochloric acid, diluted with 10 ml. of water, 
cooled, filtered, and 1 drop of potassium dichro- 
mate T.S. added to the filtrate. Loss on drying. — 
Not over 0.5 per cent on drying at 60° for 1 hour. 
Residue on ignition. — Not over 0.05 per cent. 
Readily carbonizable substances. — A solution of 
500 mg. of acetophenetidin in 5 ml. of sulfuric 
acid has no more color than matching fluid T. 
Acetanilid. — Neither turbidity nor precipitation 
results when bromine T.S. is added, dropwise, to 
the filtrate from a mixture of 500 mg. of aceto- 
phenetidin and 10 ml. of water which has been 
boiled for 1 minute, then cooled and filtered. 
U.S.P. 

Incompatibilities. — Acetophenetidin is slowly 
decomposed by strong acids and alkalies; oxidiz- 
ing agents usually produce a red color; ethyl ni- 
trite spirit causes the slow development of a yel- 
low color which deepens to reddish brown. It 
forms a wet mass when triturated with chloral 
hydrate, acetylsalicylic acid, aminopyrine, and 
many other substances. An insoluble derivative is 
formed with iodine. 

Uses. — Acetophenetidin is useful as an anti- 
pyretic and analgesic in the same group of cases 
in which acetanilid is of service. It is commonly 
prescribed in combination with other drugs such 
as acetylsalicylic acid or acetanilid, caffeine or 
citrated caffeine, and codeine sulfate, etc. Aceto- 



phenetidin, like acetanilid, yields in the body 
N-acetyl-p-aminophenol and its physiological ac- 
tion and therapeutic effects are essentially the 
same as those of acetanilid (q. v.) Its action, 
however, is more gradual and more prolonged and 
it is less likely to give rise to undesirable symp- 
toms. Only 7 of the 62 cases of sulfhemoglob- 
inemia reported by Brandenburg and Smith (see 
under Acetanilid) were associated with prolonged 
use of acetophenetidin, as compared to the 44 
cases reported from the prolonged use of ace- 
tanilid. The same increase in the threshold to the 
pain produced by radiant heat was observed by 
Wolff, Hardy and Goodell with an oral dose of 
300 mg. of acetophenetidin as was produced by 
300 mg. of acetanilid. The Food and Drug Ad- 
ministration believes that acetophenetidin may be 
a dangerous drug if the daily dose exceeds 1 Gm. 
and has expressed the following opinion: "It is 
well established that frequent or continued use of 
acetophenetidin-containing preparations may be 
dangerous, causing serious blood disturbances. 
This fact should be borne in mind in devising la- 
bels for this preparation to conform with the re- 
quirement of section 502 (f)(2) of the Act that 
the labeling of drugs bear adequate warnings." 
{Drug & Cosmetic Ind., 1941, 48, 163.) S 

The usual dose of acetophenetidin is 300 mg. 
(approximately 5 grains), with a range of 300 mg. 
to 1 Gm. A total dose in 24 hours up to 3 Gm. has 
been reported (but see above). 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

ACETOPHENETIDIN TABLETS. 
U.S.P. (B.P., LP.) 

[Tabellae Acetophenetidini] 

"Acetophenetidin Tablets contain not less than 

94 per cent and not more than 106 per cent of 
the labeled amount of C10H13O2N." U.S.P. The 
B.P. requires that Tablets of Phenacetin contain 
not less than 95.0 per cent, and not more than 
105.0 per cent, of the stated amount of phe- 
nacetin. The tablets may be prepared by moist 
granulation and compression. The LP. limits are 
94.0 and 106.0 per cent, respectively. 

B.P. Tablets of Phenacetin; Tabellae Phenacetini. LP. 
Compressi Phenacetini. Sp. Tabletas de Acetofenetidina. 

Assay. — A representative sample of tablets, 
equivalent to about 300 mg. of acetophenetidin, 
is extracted with petroleum benzin to remove 
lubricants, then with chloroform to dissolve aceto- 
phenetidin. The chloroform is evaporated and the 
residue of acetophenetidin is dried at 60° and 
weighed. U.S.P. 

In the B.P. assay the phenacetin is extracted 
from a sample of powdered tablets with hot 

95 per cent alcohol, the solution is evaporated 
and the residue washed with successive 5-ml. por- 
tions of water, previously saturated with phenace- 
tin. The washed residue is redissolved in hot 95 
per cent alcohol, the solution evaporated and the 
residue dried to constant weight at 105°. 

Usual Sizes. — 1, 2, 3, and 5 grains (approxi- 
mately 60, 120, 200, and 300 mg.). 



14 Acetophenetidin and Phenyl Salicylate Tablets 



Part I 



ACETOPHENETIDIN AND PHENYL 
SALICYLATE TABLETS. N.F. 

Phenacetin and Salol Tablets 
[Tabellae Acetophenetidini et Phenylis Salicylates] 

"Acetophenetidin and Phenyl Salicylate Tablets 
contain not less than 90 per cent and not more 
than 110 per cent of the labeled amounts of 
acetophenetidin and of phenyl salicylate." N.F. 

Tests. — Identification. — (1) The tablets re- 
spond to the identification tests under Phenyl 
Salicylate Tablets. (2) A purplish color is pro- 
duced when powdered tablets equivalent to about 
100 mg. of acetophenetidin is boiled for 1 minute 
with 1 ml. of hydrochloric acid, diluted with 10 
ml. of water, cooled, filtered, and 1 drop of po- 
tassium dichromate T.S. added to the filtrate. 
N.F. 

Assay. — For acetophenetidin. — A representa- 
tive portion of tablets, equivalent to not more 
than 80 mg. of phenyl salicylate, is extracted with 
chloroform to dissolve both the acetophenetidin 
and the phenyl salicylate. The chloroform is 
evaporated and the residue is heated for 15 min- 
utes with 2.5 per cent sodium hydroxide solution 
which hydrolyzes phenyl salicylate to sodium 
phenolate and sodium salicylate, but does not 
affect acetophenetidin. The latter is extracted 
with chloroform and, after washing each of the 
chloroform portions with water, the solvent is 
evaporated and the acetophenetidin dried at 60° 
for 1 hour and weighed. For phenyl salicylate. — 
The alkaline solution and aqueous washings re- 
maining after the extraction of acetophenetidin 
is analyzed as directed under the assay for Phenyl 
Salicylate Tablets. N.F. 

Storage. — Preserve "in tight containers at a 
temperature not above 35°." N.F. 

Usual Size. — These tablets usually contain 
2^2 grains (approximately 150 mg.) of each in- 
gredient. 

ACETRIZOIC ACID. U.S.P. 

3-Acetamido-2,4,6-triiodobenzoic Acid 




NH-CO-CH3 



"Acetrizoic Acid contains not less than 99 per 
cent of C9H6I3NO3. and not less than 67 per 
cent and not more than 68.5 per cent of iodine 
(I), calculated on the dried basis." U.S.P. 

Acetrizoic acid is the active component of so- 
dium acetrizoate injection (Urokon, Mallinck- 
rodt), a radiopaque medium described in a 
separate monograph. The acid is prepared by re- 
ducing ra-nitrobenzoic acid to w-aminobenzoic 
acid, treating with iodine monochloride to pro- 
duce 2,4,6-triiodobenzoic acid, and finally acetyl- 
ating with acetic anhydride (Wallingford, 
J.A.Ph.A., 1953, 42, 721). For detailed informa- 
tion see U. S. Patent 2,611,786 (1952). 

Description. — "Acetrizoic Acid occurs as a 
white powder. It is odorless. Acetrizoic Acid is 



slightly soluble in water. It is soluble in alcohol, 
slightly soluble in ether, very slightly soluble in 
chloroform, and practically insoluble in benzene. 
It is soluble in solutions of alkali hydroxides. 
Acetrizoic Acid melts with decomposition between 
278° and 283°." U.S.P. 

Standards and Tests. — Identification. — (1) 
On heating acetrizoic acid the substance melts to 
a dark brown liquid and liberates iodine vapors. 
(2) After preliminary hydrolysis of acetrizoic 
acid with alkali, followed by diazotization and 
coupling with betanaphthol, a white precipitate, 
which becomes purple within 5 minutes, is pro- 
duced. Loss on drying. — Not over 0.1 per cent, 
when dried at 105° for 18 hours. Heavy metals. — 
The limit is 20 parts per million. U.S.P. 

Assay. — For acetrizoic acid. — An alcohol solu- 
tion of 1 Gm. of acetrizoic acid is titrated with 
0.1 N sodium hydroxide, using phenolphthalein 
as indicator. Each ml. of 0.1 N sodium hydroxide 
represents 55.69 mg. of C9H6I3NO3. For iodine. 
— The assay for iodine specified for Iodophthalein 
Sodium is employed. U.S.P. 

For information concerning the ultimate use of 
this agent, in the form of its sodium salt, see 
under Sodium Acetrizoate Injection. 

Storage. — Preserve "in well-closed containers." 
U.S.P. 

ACETYLCHOLINE CHLORIDE. LP. 

Acetylcholine Chloridum 

CH 3 .COOCH2.CH2.N(CH 3 )3Cl 

Acetylcholine chloride is 2-acetoxyethyltri- 
methylammonium chloride; it contains not less 
than 98.0 per cent, and not more than the equiva- 
lent of 102.0 per cent, of C7H16O2NCI, calculated 
with reference to the substance dried to constant 
weight at 110°. LP. 

Acecoline (Anglo-French Laboratories) 

Acetylcholine occurs naturally in many tissues 
(see below) but for pharmacological experimenta- 
tion and therapeutic use it is prepared syntheti- 
cally, as the chloride salt. In the method most 
commonly used trimethylammonium chloride is 
interacted with ethylene oxide to form choline 
chloride, which is treated with acetic anhydride 
to form acetylcholine chloride. 

Description. — Acetylcholine chloride occurs 
as white, odorless, very hygroscopic crystals. It 
is very soluble in water, in alcohol, in chloroform, 
and in acetic acid; it is insoluble in ether and in 
benzene. Acetylcholine chloride, after drying at 
110°, melts between 149° and 152°. 

Standards and Tests.— Identification. — (1) 
Trimethylamine, recognizable by its odor, is 
evolved when acetylcholine chloride is heated with 
sodium hydroxide T.S. (2) An aqueous solution 
of acetylcholine chloride yields a precipitate with 
phosphotungstic acid T.S., with trinitrophenol 
T.S., and with iodine T.S. (3) It responds to tests 
for chloride and, after alkaline hydrolysis, to tests 
for acetate. Reaction. — A 10 per cent w/v solu- 
tion in water is neutral to litmus T.S. Arsenic. — 
The limit is 2 parts per million. Heavy metals — 
The limit is 10 parts per million. Lead. — The limit 
is 10 parts per million. Free acid. — Not more than 



Part I 



Acetylsalicylic Acid 15 



0.2 ml. of 0.01 N sodium hydroxide produces a 
red color in a solution of 100 mg. of acetylcholine 
chloride in 10 ml. of recently boiled and cooled 
water to which 1 drop of phenolphthalein T.S. has 
been added. Trimethylamine. — No odor of that 
substance is apparent on boiling a solution of 
100 mg. of acetylcholine chloride in 10 ml. of 
saturated solution of sodium carbonate. Loss on 
drying. — Not over 0.75 per cent when dried to 
constant weight at 110°. Residue on ignition. — 
Not over 0.1 per cent. LP. 

Assay. — About 100 mg. of acetylcholine chlo- 
ride, dissolved in boiled and cooled distilled water, 
is boiled under reflux for 15 minutes with 10 ml. 
of 0.1 N carbonate-free sodium hydroxide, which 
releases acetic acid by hydrolysis. The excess of 
alkali is titrated with 0.1 N sulfuric acid, using 
phenolphthalein T.S. as indicator. Each ml. of 
0.1 N sodium hydroxide represents 18.17 mg. of 
C7H16O2NCI. LP. 

Action of Acetylcholine. — Acetylcholine, 
CH 3 .COOCH2.CH 2 N(CH3)30H, is now gener- 
ally considered to be the chemical mediator of 
the parasympathetic postganglionic, the auto- 
nomic (sympathetic and parasympathetic) pre- 
ganglionic and motor nerve impulses. When one 
of these nerves, as for example the vagus, is 
stimulated, there is formed at the peripheral ter- 
minations a substance which appears to be acetyl- 
choline, and which is generally believed to act 
upon the parenchyma of the organ under consid- 
eration (see under Parasympathomimetic Agents 
and Cholinesterase Inhibitors). After excitation 
of the nerve ceases there is a rapid breakdown of 
the compound, effected by the presence of the 
enzyme cholinesterase (see Koppanyi and associ- 
ates, /. Pharmacol, 1953, 107, 482, 501). As a 
result of this enzyme-catalyzed hydrolytic action, 
the acetyl radical is split off, leaving choline, 
which is comparatively inert. 

If acetylcholine is injected into the circulation 
it will cause all the characteristic effects of elec- 
trical stimulation of all the parasympathetic 
nerves, such as slowing of the pulse, vasodilata- 
tion, fall in blood pressure, bronchospasm, in- 
creased bronchial secretion, hyperpnea, increased 
gastric secretion, increased tone and peristaltic 
contractions of the gastrointestinal tract, increased 
secretion of sweat, tears and saliva, contraction 
of pupils, etc. (Koppanyi, Bull. Johns Hopkins 
Hosp., 1948, 83, 532). In larger doses, acetyl- 
choline excites the sympathetic ganglia, producing 
a very definite group of reactions which resemble 
those of nicotine. Large doses of acetylcholine 
also cause reactions of the voluntary muscles. 
This contraction of skeletal muscle has led to the 
basic concept of cholinergic (acetylcholine) me- 
diation of motor impulses to skeletal muscles (see 
under Curarimimetic Agents) ; for further infor- 
mation see Feldberg, Physiol. Rev., 1945, 25, 
596, also Lorente de No, Bull. Johns Hopkins 
Hosp., 1948, 83, 497). Welsh {ibid., 568) con- 
cluded that acetylcholine acts on all cells of the 
body to alter the excitability of the cell through 
change of membrane polarity and permeability. 
Acetylcholine is also important in the transmission 
of the nerve impulse along the axone (Nachman- 
sohn, ibid., 1948, 83, 463). 



Uses. — Acetylcholine has been employed to 
some extent as a therapeutic remedy in various 
acute conditions in which stimulation of the au- 
tonomic nervous system is desirable. It has been 
used for tobacco amblyopia (Duggan, J.A.M.A., 
1937, 109, 1354), paroxysmal auricular tachy- 
cardia (Abbott, ibid., 1939, 113, 1243), acropares- 
thesia (Ekbom, Acta psychiat. neurol., 1939, 14, 
311), and paralytic ileus (Abel, Lancet, 1933, 2, 
1252). The extreme evanescence of its action and 
the marked stimulation of the autonomic ganglia 
from overdoses have greatly restricted its value. 
Methacholine chloride and carbachol are gener- 
ally preferred. Drugs which inhibit cholinesterase, 
such as neostigmine and physostigmine, are more 
widely used. S 

The dose of acetylcholine chloride is 50 mg. 
initially, then 100 mg. daily, subcutaneously or 
intramuscularly. At the most, 200 mg. (approxi- 
mately 3 grains) is given. It should not be 
administered intravenously because less than 
one-tenth these quantities will cause marked 
physiological reactions. When using the drug it 
is advisable to have a solution of atropine ready 
for immediate administration if it is necessary to 
counteract the effects of acetylcholine. 

Acetylcholine chloride, because of its pro- 
nounced hygroscopicity and the instability of its 
aqueous solutions, is supplied in ampuls contain- 
ing 100 mg. of the crystals, from which a solution 
may be prepared as required. Under the name 
Acecoline a propylene glycol solution containing 
in 1 ml. 20 mg., 50 mg., 100 mg., or 200 mg., with 
saligenin, is also marketed. 

Storage. — Acetylcholine chloride should be 
kept in a tightly-closed container. LP. 

ACETYLSALICYLIC ACID. 
U.S.P., B.P., LP. 

Aspirin, [Acidum Acetylsalicylicum] 



C00H 




O-CO-CH3 



"Acetylsalicylic Acid, dried over sulfuric acid 
for 5 hours, contains not less than 99.5 per cent of 
CoHsOi." U.S.P. The B.P. assay rubric is the 
same, but the chemical is not required to be dried. 
The LP., which defines the compound as 2-acet- 
oxybenzoic acid, likewise requires not less than 
99.5 per cent purity, the substance not being 
dried. 

Fr. Acide acetylsalicylique ; Aspirine. Ger. Acetylsali- 
zylsaure. It. Acido acetilsalicilico. Sp. Acido acetil- 

salicilico; Acido salicilacetico; Aspirina. 

Acetylsalicylic acid had been synthesized some 
years before it was introduced into medicine, in 
1899, by Dreser. The name aspirin, by which this 
substance is popularly known, is not purely fanci- 
ful nor arbitrary. It is derived from the fact that 
salicylic acid, as originally obtained from Spiraa 
ulmaria, was at first known as acidum spiricum. 
Acetylsalicylic acid may be prepared by acetyliz- 
ing salicylic acid by means of acetic anhydride or 
acetyl chloride, the former being the more fre- 
quently used because of its greater economy. An 



16 Acetylsalicylic Acid 



Part I 



excess of acetic anhydride is heated with salicylic 
acid at a temperature of about 150° for three 
hours; the excess of the anhydride, as well as 
acetic acid formed in the reaction, is removed by 
distillation, and the residue of acetylsalicylic acid 
is purified by recrystallization from a non-aqueous 
solvent. Acetylsalicylic acid cannot be purified 
by crystallization from water or solvents contain- 
ing it because of its tendency to undergo hydrol- 
ysis. It may be crystallized from benzene, methyl 
acetate, chloroform, or strong ethyl or methyl 
alcohol. 

Patents have been granted in this country and 
in Great Britain for a process whereby salicylic 
acid is dissolved in an inert solvent, such as dry 
ethyl ether, through which ketene. a gas having the 
chemical formula CH2:CO, is passed until the 
solution is saturated. Upon evaporating the ether, 
needle-like crystals of acetylsalicylic acid are ob- 
tained. The chemical reaction takes place accord- 
ing to the following equation: 

CeEUOH.COOH + CH 2 :CO -* 

C 6 H4.0(CH 3 CO).COOH 

Description. — "Acetylsalicylic Acid occurs as 
white crystals, commonly tabular or needle-like, 
or as a white, crystalline powder. It is odorless or 
has a faint odor. It is stable in dry air; in moist 
air it gradually hydrolyzes to salicylic and acetic 
acids. One Gm. of Acetylsalicylic Acid dissolves 
in about 300 ml. of water, in 5 ml. of alcohol, in 
17 ml. of chloroform, and in from 10 to 15 ml. of 
ether. It is less soluble in absolute ether. Acetyl- 
salicylic Acid dissolves with decomposition in 
solutions of alkali hvdroxides and carbonates." 
U.S.P. 

The B.P. gives the melting point as from 135° 
to 138° C. Considerable variation exists in the 
reported values of the melting point of aspirin, 
some investigators claiming it to be 131° to 
132° C.. while others claim 134° to 135° C. Beal 
and Szalkowski (/. A. Ph. A., 1933, 22, 36) be- 
lieve that these differences are due to the fact that 
some decomposition occurs during the process of 
heating the acid to the melting temperature, and 
also that excessive trituration to produce a fine 
powder results in partial decomposition. Both 
effects are evidenced by a lowered melting point. 
The composition of the glass used for the melting 
point tube may influence the melting point of 
acetylsalicylic acid; Pyrex glass appears to be 
without effect. 

Standards and Tests. — Identification. — (1) 
A violet red color is produced when acetylsalicylic 
acid is heated with water for several minutes, 
cooled, and a drop or two of ferric chloride T.S. 
added. (2) When 500 mg. of acetylsalicylic acid 
is hydrolyzed by boiling with 10 ml. of sodium 
hydroxide T.S., the solution cooled and acidified 
with 10 ml. of diluted sulfuric acid a white pre- 
cipitate of salicylic acid is obtained, and the odor 
of acetic acid is developed. If the mixture is 
filtered, and 3 ml. of alcohol and 3 ml. of sulfuric 
acid are added to the filtrate an odor of ethyl 
acetate develops on warming the mixture. Loss on 
drying. — Acetylsalicylic acid loses not more than 
0.5 per cent of its weight on drying over sulfuric 



acid for 5 hours. Residue on ignition. — Not over 
0.05 per cent. Readily carbonizable substances. — 
A solution of 500 mg. of acetylsalicylic acid in 
5 ml. of sulfuric acid has no more color than 
matching fluid Q. Chloride. — The limit is 140 
parts per million. Sulfate. — The limit is 400 parts 
per million. Free salicylic acid. — The limit is 0.1 
per cent. Heavy metals. — The limit is 10 parts per 
million. Substances insoluble in sodium carbonate 
T.S. — A portion of 500 mg. of acetylsalicylic acid 
should form a clear solution with 10 ml. of warm 
sodium carbonate T.S. U.S.P. 

The B.P. tests differ from corresponding de- 
scriptions and tests of the U.S.P. only in minor 
details, except that the former permits but half 
the amount of salicylic acid allowed by the U.S.P. 
An arsenic limit of 2 parts per million and a limit 
of lead of 10 parts per million are provided. 

Assay. — The U.S.P. directs that about 1.5 Gm. 
of acetylsalicylic acid, previously dried over sul- 
furic acid for 5 hours, be boiled for 10 minutes 
with 50 ml. of 0.5 N sodium hydroxide and the 
excess base determined by titration with 0.5 N 
sulfuric acid using phenolphthalein as indicator. 
In this assay the acetylsalicylic acid is hydrolyzed 
to form the sodium salts of acetic and salicylic 
acids; the reliability of the assay is dependent on 
having a sample which has not decomposed beyond 
the permitted limit. A residual blank titration is 
performed. Each ml. of 0.5 N sodium hydroxide 
represents 45.04 mg. of C9HSO4. U.S.P. 

The B.P. assay is the same as that of the U.S.P. 
except that phenol red is employed as indicator. 
The LP. assay is also the same, phenolphthalein 
indicator being used. 

Incompatibilities. — Acetylsalicylic acid read- 
ily undergoes hydrolysis with aqueous solvents 
with liberation of salicylic and acetic acids. In 
pure water complete decomposition takes place 
in 100 days. Acids hasten the rapidity of such 
change. Alkalies and solutions of alkaline acetates 
and citrates dissolve acetylsalicylic acid, but the 
resulting solutions hydrolyze rapidly to form salts 
of acetic and salicylic acids. The decomposition 
may be retarded somewhat by glycerin and sugar. 
Liquefaction occurs when acetylsalicylic acid is 
triturated with phenyl salicylate, acetanilid, aceto- 
phenetidin. aminopyrine., antipyrine and many 
other organic products. Partial hydrolysis occurs 
in mixtures of acetylsalicylic acid with hygro- 
scopic substances or salts containing water of 
hydration. Hydriodic acid is slowly produced from 
iodides and subsequent oxidation by the air liber- 
ates iodine. 

The statement that quinine and acetylsalicylic 
acid react upon each other to form the poisonous 
quinotoxin has been contradicted by the experi- 
ments of Sollmann. Ruddiman and Lanwermeyer 
(/. A. Ph. A., 1924, 13, 1009) experimented with 
mixtures of acetylsalicylic acid with basic quinine 
and also the sulfate, bisulfate. hydrochloride and 
other cinchona alkaloids. They found that the 
mixture with quinine alkaloid, after several 
months, changed to a brownish red viscid mass if 
exposed to the light, but when kept in the dark 
the change was less rapid; this mixture tested on 
frogs was not more poisonous than the freshly 



Part I 



Acetyl salicylic Acid 17 



made mixture nor than the equivalent dose of ace- 
tylsalicylic acid. 

It has been reported that morphine and codeine 
form poisonous compounds with this drug. 

Uses (see also Salicylic Acid and Sodium 
Salicylate). — The antipyretic effect of willow bark 
was known to the ancients and, early in the 19th 
century, salicylic acid was prepared from salicin, 
a glycoside from this bark. Acetylsalicylic acid 
was introduced into medicine in 1899. 

Metabolism. — Acetylsalicylic acid is absorbed 
as such from the gastrointestinal tract (Bradley 
et al., Am. J. Digest. Dis., 1936, 3, 415) and 
transported throughout the tissues as the sodium 
salt, appearing in the joints, the pleura, etc. Fol- 
lowing doses of 10 Gm. daily, the salicylate con- 
centration in the blood ranges from 30 to 50 mg. 
per 100 ml. {J. A.M. A., 1945, 128, 1195). The 
simultaneous administration of sodium bicar- 
bonate in equivalent dosage decreases the blood 
concentration almost one-half (Smull et al., 
J.A.M.A., 1944, 125, 1173; but see Lester et al, 
J. Pharmacol, 1946, 87, 329). About £0 per cent 
of the drug is excreted in the urine, making its 
appearance within 10 to 15 minutes after ingestion 
(/. Pharmacol, 1919, 14, 25). Excretion is almost 
complete within a few hours although traces ap- 
pear in the urine during several days. In febrile 
patients only 60 to 70 per cent is excreted. From 
10 to 35 per cent of the ingested acetylsalicylic 
acid appears in the urine unchanged or as the 
sodium salt; some is present as a glucuronate. 
Such urine reduces Benedict's solution and gives 
a violet color with ferric chloride. 

Therapeutic Actions. — Acetylsalicylic acid is 
used medicinally for several purposes. 

Antipyretic. — The antipyretic effect of acetyl- 
salicylic acid arises from its action on the central 
nervous system. Barbour {Arch. Int. Med., 1919, 
24, 617 and 624; Physiol. Rev., 1921, 1, 295) 
showed that it facilitates dissipation of heat 
through increased peripheral blood flow, hydration 
of the blood, and sweating. Although sponges with 
tepid water or alcohol are effective for the reduc- 
tion of temperature, acetylsalicylic acid is com- 
monly used and is simpler when the discomfort 
arising from fever is great, as in influenza, or when 
prolonged high fever may be deleterious to the 
general welfare of the patient. Weakness may be 
aggravated by sweating and the water and salt so 
lost should be replaced. Therapeutic doses have 
no effect on the cardiovascular system. 

Analgesic. — Acetylsalicylic acid alleviates pain 
by a depressant action on the central nervous sys- 
tem, probably on the thalamus; Lester et al. 
(J. Pharmacol, 1946. 87, 329) believe its action 
to be exercised mainly by the unhydrolyzed frac- 
tion in the plasma. Integumental pain such as 
myalgia, arthralgia, headache, etc., responds better 
than does pain of visceral origin. Although it has 
little local anesthetic action, acetylsalicylic acid is 
sometimes employed as a gargle or a chewing gum 
with symptomatic relief of sore throat. It is prob- 
ably the most commonly used analgesic, being 
prescribed alone or in combination with aceto- 
phenetidin, codeine, caffeine, amphetamine and 
other drugs. 



The threshold for cutaneous pain through heat 
is increased about 35 per cent within 50 to 100 
minutes after oral doses of 65 to 300 mg., the 
effect lasting for about 2 hours. In comparison, 
15 mg. of morphine sulfate injected intramuscu- 
larly increases the threshold about 70 per cent 
(Wolff, Hardy and Goodell, /. Clin. Inv., 1941, 
20, 63). Unfortunately, evaluation of analgesic 
drugs according to their ability to depress the 
threshold of pain perception caused by radiant 
heat applied to the skin of normal subjects or 
animals has not been proved to be an accurate 
prediction of their efficacy in patients with pain 
due to injury or disease. Beecher (Science, 1952, 
116, 157) and his associates have struggled with 
the evaluation of the subjective phenomenon of 
pain in sick patients. In attempting to establish 
criteria for effectiveness of an analgesic agent he 
denied the validity of measuring sensory percep- 
tion of pain produced by heat in normal subjects. 
Letters to the editor by Hardy, Wolff and Goodell 
(Science, 1953, 117, 164) and Beecher (ibid., 
166) have debated the issue to little, if any, prac- 
tical conclusion. Ravich (ibid., 118, 144) com- 
ments that "physiological" pain produced by heat 
on normal tissue is a normal sensory response 
whereas "pathological" pain caused by disease is 
an abnormal phenomenon with many more un- 
known features. Beecher comments that so-called 
"common sense" in hundreds of years of clinical 
practice has arrived at an average effective dose 
of morphine (15 mg.) which is twice as large as 
the one (8 mg.) which gives essentially maximum 
pain relief in his complicated, controlled studies 
of hospital patients. It can only be concluded that 
adequate methods of evaluating analgesic drugs 
remain to be developed. Furthermore, the physi- 
cian is desirous of relieving pain in his patient 
rather than using a dose which will relieve pain in 
nearly all patients in the statistical sense but 
which might fail in his particular patient. 

Acetylsalicylic acid relieves the aching and the 
fever of "grippe" although it does not shorten the 
course of the illness. 

Antirheumatic. — Acetylsalicylic acid (see also 
Sodium Salicylate) is the drug most generally 
employed in the treatment of acute rheumatic 
fever. Larger doses are administered than in most 
other conditions, from 1 to 1.3 Gm. (approxi- 
mately 15 to 20 grains) being given hourly until 
the acute joint symptoms are relieved. About 10 
doses are usually required. If toxic symptoms ap- 
pear the drug is discontinued for 12 hours, then 
given in doses of 1 Gm. every 4 hours, six times 
daily, until evidence of active rheumatic fever 
has been absent for 1 week (McEwen, Bull N. Y. 
Acad. Med., 1943, 19, 679). The mechanism of 
the almost specific action of salicylates in acute 
rheumatic fever is unknown; morphine, for ex- 
ample, relieves the pain but not the swelling, 
redness and increased heat of the joints. How- 
ever, salicylates do not shorten the course of the 
disease or prevent cardiac and other complica- 
tions. There are general similarities between the 
effects of salicylates and cortisone. Both relieve 
pain, produce a fall in temperature, reduce the 
erythrocyte sedimentation rate and prevent re- 



18 Acetylsalicylic Acid 



Part I 



lapse of the rheumatic state as long as adminis- 
tration is continued. Pfeiffer (/. Pharmacol., 1950. 
98, 26) demonstrated an increase in eosinophil 
count after administration of acetylsalicylic acid. 
An increase in urinary excretion of reducing ster- 
oids following the use of acetylsalicylic acid has 
been reported by Van Cauwenberge (Lancet, 
1951, 260, 771; Acta M. Scand., 1952, 141, 265). 
Mild Cushing's syndrome is reported to have 
followed acetylsalicylic acid therapy in acute 
rheumatic fever (Cochran, Brit. M. J., 1950, 2, 
1411). Pelloja (Lancet, 1952, 262, 233) found 
salicylates capable of inhibiting the action of 
hyaluronidase in a manner similar to cortisone. 
Whether these effects are primary or are medi- 
ated through cortisone release awaits further 
elucidation. Actually, in a large cooperative study 
of the effect of corticotropin, cortisone and acetyl- 
salicylic acid (Houser et al., Am. J. Med., 1954. 
16, 168). the results failed to demonstrate supe- 
rior efficacy for, any of the 3 drugs both as to 
controlling the acute symptoms and the duration 
of the active disease. In other forms of poly- 
arthritis (gonorrheal, streptococcal, meningococ- 
cal, etc.) salicvlate therapy induces less dramatic 
relief (Cecil, JAMA., 1940. 114, 1443). In acute 
rheumatic fever Coburn (Bull. Johns Hopkins 
Hosp., 1943, 73, 435) reported excellent results 
from doses of salicylates sufficient to maintain a 
blood concentration of 30 to 50 mg. per 100 ml. 
but Wegria and Smull (J. AM. A., 1945, 129, 485) 
and others failed to confirm the shorter course of 
the disease and the decreased incidence of endo- 
cardial damage. With doses of 10 Gm. or more 
daily, the danger of salicylism requires careful 
observation of the patient. Salicylates increase 
excretion of ascorbic acid (Samuels et al., J. Phar- 
macol, 1940, 68, 465), but correction of the de- 
ficiency permits continuation of therapy. 

Acute intraocular inflammation such as uveitis 
responds well to large doses of salicylates 
(JAMA., 1920, 75, 725; 1939, 113, 928"). In 
lumbago, pleurodynia and other myalgias, in cer- 
tain inflammations of nerves such as sciatica, in 
some instances of rheumatoid arthritis and osteo- 
arthritis, and in the host of similar conditions 
which, for want of better diagnostic acumen, we 
are wont to call rheumatism, acetylsalicylic acid 
is a valuable palliative drug. 

Action on the Kidney. — A single dose of acetyl- 
salicylic acid increases the renal excretion of uric 
acid by 30 to 50 per cent and often decreases the 
concentration of uric acid in the blood, an effect 
probably due to a decrease in tubular resorption 
of uric acid. This action persists on repeated ad- 
ministration if the diet contains sufficient purines. 
Hanzlik and Scott (Arch. Int. Med.. 1917, 20, 
329) found albumin, with or without casts, and 
red and white cells in the urine after doses of 
more than 3 Gm. In salicylism. water retention 
by the kidney, manifested by increase in body 
weight but not by actual pitting edema, was also 
described. In current experience, albuminuria and 
other evidences of renal damage are extremely 
rare even with doses of 6 to 10 Gm. dailv 
(J.A.M.A., 1945, 128, 1195). In gout, acetyl'- 
salicylic acid in large doses relieves the acute 
attacks but is less effective than colchicum. It is 



also less effective than cinchophen or probenecid 
in the prevention of recurrent attacks in the course 
of the disease (Hench, Proc. Mayo, 1937, 12, 
262).® 

Toxicology. Acetylsalicylic acid is not highly 
toxic. Hopkins (Lancet, 1945, 1, 145) records 50 
deaths in England in 5 years, a figure not unduly 
large in view of the wide use of the drug and the 
large doses sometimes employed (see also Green- 
berg, New Eng. J. Med., 1952, 243, 124;. It is 
frequently taken in very large doses with suicidal 
intent but usually without success (J.A.M.A., 
1936, 107, 276; Ruttan, Can. Med. Assoc. J., 
1952. 67, 151). A single dose of 10 to 30 Gm. is 
likely to be fatal although survivals after larger 
doses and deaths from smaller ones have been 
reported. Impaired renal function enhances the 
toxicity. A total of 12 Gm. during 24 hours usu- 
ally produces symptoms of salicylism such as 
tinnitus, vertigo, impaired hearing and headache. 
More severe manifestations include hyperpnea. 
fever and acidosis and, less regularly, dimness of 
vision, sweating, thirst, nausea, vomiting, diarrhea, 
skin rashes, tachycardia, restlessness, delirium 
and hallucinations. Salicylism may resemble dia- 
betic or renal acidosis. In the worst cases, depres- 
sion, stupor, coma, cardiovascular collapse, con- 
vulsions and respiratory failure follow. Fatal cases 
show diffuse endothelial damage with petechial 
hemorrhage and congestion throughout the vis- 
cera (Troll and Menton, Am. J. Dis. Child., 1945, 
69,37). 

Treatment. — Treatment of acute poisoning in- 
volves the prompt removal of the unabsorbed 
drug by gastric lavage and the administration of 
30 Gm. of magnesium sulfate. Water and sodium 
chloride are replaced parenterally and intravenous 
glucose, one-sixth molar sodium r-lactate. and 
vitamin K given as required. High fever should 
be controlled with tepid sponges. Sedation may 
be required for some patients; for others caffeine 
or ephedrine are needed to overcome depression. 

Complications. — Although most tests of liver 
function show no abnormality, large doses of 
salicylates may depress the prothrombin activity 
of the blood (Smith, Lancet, 1951. 261, 569; 
Field, Am. J. Physiol, 1949, 159, 40; Schaeffer. 
/. Maine M. A., 1951, 42, 262). Hemorrhagic 
tendencies following the use of acetylsalicylic acid 
in post-tonsillectomv cases have been reported 
(Jones, South. M. J ., 1949. 42, 124). Decreased 
prothrombin activity may also be responsible in 
part for the hemorrhagic manifestations of sali- 
cylism and it may aggravate the hemorrhagic 
tendencv of the rheumatic state (Clever-Howard. 
Proc. S. Exp. Biol. Med., 1943. 53, 234). Hypo- 
pro thrombinemia is prevented by simultaneous 
administration of 1 mg. of menadione for each 
1 Gm. of salicvlate (Shapiro. JAMA., 1944, 
125, 546: Emerson. JAMA., 1952. 149, 348). 

Large doses of acetylsalicylic acid frequently 
lead to gastric distress. Sodium bicarbonate may 
be used to alleviate this distress but it should be 
pointed out that its use may decrease the blood 
concentration of acetylsalicylic acid. Various 
other buffering systems are used to alleviate this 
distress, including aluminum dihydroxyamino- 
acetate and magnesium carbonate, which is also 



Part I 



Acetylsalicylic Acid, Acetophenetidin and Caffeine Capsules 19 



said to increase salicylate absorption from the 
gastrointestinal tract (Paul, J. A. Ph. A., 1950, 
39, 21; Tebrock, Ind. Med., 1951, 20, 480). 

Allergy. — Idiosyncrasy to acetylsalicylic acid 
is rare {Am. J. Med. Sc, 1940, 200, 390; and is 
most frequently observed in asthmatics and espe- 
cially in those with nasal polyps (J.A.M.A., 1937, 
108, 445; Ann. Int. Med., 1947, 26, 734; Can. 
Med. Assoc. J., 1951, 64, 187). The manifesta- 
tions are urticaria, erythema, desquamative or 
bullous or purpuric skin lesions, angioneurotic 
edema, laryngeal stridor, asthma and peripheral 
vascular collapse. These reactions are often seri- 
ous and frequently fatal. Hypodermic or intra- 
venous epinephrine is usually an effective treat- 
ment. In milder cases antihistaminic drugs may 
be useful. As a test for sensitivity, Duke advised 
placing one-eighth of a tablet in the mouth; in 
hypersensitive persons symptoms appear in one 
minute and the rest of the tablet can be rinsed 
from the mouth with water. 

Dose. — The usual dose is 600 mg. (approxi- 
mately 10 grains) by mouth every 4 hours, as 
necessary, with a range of 300 to 900 mg. Ordi- 
narily the maximum safe dose is 1 Gm. and it is 
seldom that a total dose of more than 10 Gm. in 
24 hours is employed. In acute rheumatic fever, 
300 mg. to 1.3 Gm. (approximately 5 to 20 grains) 
may be given every hour until a daily total of 
about 10 Gm. has been given. Children tolerate 
proportionately larger doses. Sodium bicarbonate 
is often administered in equal amount with each 
dose to lessen gastric irritation. 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

ACETYLSALICYLIC ACID 
CAPSULES. N.F. 

Aspirin Capsules 

"Acetylsalicylic Acid Capsules contain not less 
than 93 per cent and not more than 107 per cent 
of the labeled amount of C9H8O4." N.F. 

Usual Size. — 5 gr. (approximately 300 mg.). 

ACETYLSALICYLIC ACID TABLETS 

U.S.P. (B.P., LP.) 

Aspirin Tablets [Tabellae Acidi Acetylsalicylici] 

"Acetylsalicylic Acid Tablets contain not less 
than 95 per cent and not more than 105 per cent 
of the labeled amount of C 9 H 8 04." U.S.P. The 
corresponding B.P. limits are 94.5 per cent and 
105.0 per cent; the LP. limits are the same as 
those of the U.S.P. 

B.P. Tablets of Acetylsalicylic Acid. LP. Compressi 
Acidi Acetylsalicylici. Sp. Tabletas de Acido Acetilsalicilico. 

Assay. — A representative sample of tablets, 
equivalent to about 500 mg. of acetylsalicylic 
acid, is mixed with neutralized alcohol, cooled to 
from 15° to 20°, and titrated with 0.1 N sodium 
hydroxide T.S., using phenolphthalein T.S. as in- 
dicator. In this titration the carboxyl group of 
acetylsalicylic acid is neutralized, as well as any 
acetic and salicylic acids that may be present. To 
the mixture is added a volume of 0.1 N sodium 
hydroxide equal to that used in the titration, plus 
15 ml. more; the mixture is heated in a boiling 



water bath for 15 minutes to convert the sodium 
acetylsalicylate to sodium acetate and sodium 
salicylate. After cooling the mixture to room tem- 
perature the excess of alkali is titrated with 0.1 iV 
sulfuric acid, using phenolphthalein T.S. as in- 
dicator. A volume of 0.1 N sodium hydroxide 
equal to that added the second time is then mixed 
with the same volume of alcohol as used in the 
test, diluted with water to the same volume and 
heated for the same period of time, then titrated 
with 0.1 N sulfuric acid. Each ml. difference in 
the two titration figures corresponds to 18.02 mg. 
of C9H.8O4, U.S.P. 

The B.P. assay is essentially the same as the 
B.P. employs for acetylsalicylic acid. The validity 
of the assay is established by providing a limiting 
test for salicylic acid. 

Usual Sizes. — 1, 2% and 5 grains (approxi- 
mately 60, 150 and 300 mg.). 

ACETYLSALICYLIC ACID, ACETO- 
PHENETIDIN AND CAFFEINE 
CAPSULES. N.F. 

Aspirin, Phenacetin, and Caffeine Capsules; 
APC Capsules 

"Acetylsalicylic Acid, Acetophenetidin and Caf- 
feine Capsules contain not less than 90 per cent 
and not more than 110 per cent of the labeled 
amounts of acetylsalicylic acid (C9H8O4), aceto- 
phenetidin (C10H13NO2), and caffeine (CsHio- 
N4O2." N.F. 

Assay. — For acetylsalicylic acid. — A chloro- 
form solution containing all three active ingredi- 
ents is shaken with a sodium bicarbonate solution, 
which removes the acetylsalicylic acid. Sodium 
hydroxide is added to the aqueous solution, which 
is heated to hydrolyze the acetylsalicylic acid; the 
resulting salicylate is determined by reaction with 
a measured excess of 0.1 N bromine, in the pres- 
ence of acid, which forms tribromophenol and 
carbon dioxide. Excess bromine is estimated by 
its releasing an equivalent amount of iodine, which 
is titrated with 0.1 N sodium thiosulfate. The 
equivalent weight of acetylsalicylic acid in this 
reaction is one-sixth its molecular weight. For 
acetophenetidin and caffeine. — The chloroform 
solution remaining after extraction of acetylsali- 
cylic acid is evaporated to dryness and the residue 
of acetophenetidin and caffeine thus obtained is 
weighed. The residue is dissolved in a small vol- 
ume of alcohol, and a measured volume of water 
is added to precipitate acetophenetidin, which is 
removed by filtration. To a portion of the filtrate 
a measured excess of 0.1 N iodine is added to 
precipitate the caffeine; this precipitate is filtered 
off and the excess iodine in a portion of the fil- 
trate is titrated with 0.05 N sodium thiosulfate. 
The equivalent weight of caffeine is one-fourth 
its molecular weight, based on the formation of 
C8H10N4O2.HI.I4. The weight of acetopheneti- 
din is calculated by subtracting the weight of 
caffeine found from the combined weight of 
acetophenetidin and caffeine. N.F. 

Uses. — Combinations of acetylsalicylic acid, 
acetophenetidin and caffeine find wide usage as 
analgetics. It would appear that inclusion of caf- 
feine enhances the overall analgetic effect in clini- 
cal usage, though it is difficult to evaluate the 



20 Acetylsalicylic Acid, Acetophenetidin and Caffeine Capsules 



Part I 



effect quantitatively and it is not apparent what 
the mechanism may be. Some clinicians do not 
believe that caffeine contributes to the efficacy 
of the preparation. For a discussion of the actions 
and uses of the component drugs see the respec- 
tive monographs for each. 

Storage. — Preserve "in well-closed containers." 
N.F. 

ACETYLSALICYLIC ACID, ACETO- 
PHENETIDIN AND CAFFEINE 
TABLETS. N.F. 

Aspirin, Phenacetin, and Caffeine Tablets; APC Tablets 

"Acetylsalicylic Acid, Acetophenetidin and Caf- 
feine Tablets contain not less than 90 per cent 
and not more than 110 per cent of the labeled 
amounts of acetylsalicylic acid (CoHsO.*), aceto- 
phenetidin (C10H13NO2), and caffeine (CsHio- 
N4O2)." N.F. 

For assay and uses see the preceding mono- 
graph. 

Storage. — Preserve "in well-closed containers." 
N.F. 

Usual Size. — Tablets containing 180 mg. (ZYi 
grains) of acetylsalicylic acid, ISO mg. (2y 2 
grains) of acetophenetidin, and 30 mg. (V2 grain) 
of caffeine. 

TABLETS OF ACETYLSALICYLIC 
ACID AND PHENACETIN. B.P. 

Tablets of Aspirin and Phenacetin, Tabellae Acidi 
Acetylsalicylici et Phenacetini 

The B.P. provides a formula from which tab- 
lets, each containing 226.8 mg. (3j^ grains) of 
acetylsalicylic acid and 162 mg. {2Yi grains) of 
phenacetin, may be prepared. The content of 
acetylsalicylic acid is required to be within the 
limits of 94.5 to 105.0 per cent and that of phe- 
nacetin within the limits of 95.0 to 105.0 per cent 
of the amounts specified, respectively, by the 
formula. 

Tests and Assay. — The presence of acetyl- 
salicylic acid is confirmed by chemical identifica- 
tion tests, while that of phenacetin is established 
by specifying that the melting point of the residue 
obtained in the assay for phenacetin shall be 
about 134°. 

In the assay for acetylsalicylic acid a repre- 
sentative sample of tablets is alkalinized with 
sodium hydroxide solution and the phenacetin is 
extracted with chloroform, which solution is set 
aside. The acetylsalicylic acid in the aqueous 
solution is completely hydrolyzed by heating the 
alkaline solution and the resulting salicylic acid 
determined by adding an excess of 0.1 N bromine, 
which forms tribromophenol and carbon dioxide; 
the excess of bromine is measured through release 
of an equivalent amount of iodine, which is 
titrated with 0.1 TV sodium thiosulfate. The 
equivalent weight of acetylsalicylic acid in this 
assay is one-sixth of its molecular weight, since 
three molecules of bromine react with a molecule 
of salicylic acid. To assay for phenacetin the 
chloroform solution set aside in the preceding 
assay is evaporated to dryness and the residue 
of acetophenetidin weighed after drying at 105°. 
B.P. 



This is a popular analgesic combination for 
which the B.P. gives the dose as 1 or 2 tablets. 

TABLETS OF ACETYLSALICYLIC 

ACID WITH IPECACUANHA 

AND OPIUM. B.P. 

Tablets of Aspirin and Dover's Powder, Tabellae Acidi 
Acetylsalicylici cum Ipecacuanha et Opio 

The B.P. provides a formula from which tab- 
lets, each containing 162 mg. {2]/ 2 grains) of 
acetylsalicylic acid and 162 mg. (2y 2 grains) of 
Powder of Ipecacuanha and Opium, may be 
prepared. The content of acetylsalicylic acid is 
required to be within the limits of 94.5 to 105.0 
per cent of the amount of that substance speci- 
fied, and that of anhydrous morphine, C17H19- 
NO3, within the limits of 0.90 to 1.10 per cent 
of the amount of powder of ipecacuanha and 
opium specified by the formula. 

Tests and Assay. — Identification tests for 
the several constituents are provided. In the 
assay for acetylsalicylic acid a representative 
portion of the powdered tablets is heated with 
dilute sulfuric acid, which effects hydrolysis of 
the aspirin to acetic and salicylic acids. The latter 
is extracted with ether, which is then extracted 
with a sodium hydroxide solution, and the sali- 
cylic acid finally determined as explained in the 
assay for Tablets of Acetylsalicylic Acid and 
Phenacetin. An assay for morphine is performed 
by the method employed in the assay for Powder 
of Ipecacuanha and Opium. B.P. 

This combination is employed as an anti- 
pyretic in the treatment of acute febrile condi- 
tions; the dose is 1 or 2 tablets. 

ACONITE. N.F. (LP.) 

Aconite Root, Monkshood, Aconiti tuber, [Aconitum] 

"Aconite is the dried tuberous root of Acotiitum 
Napellus Linne (Fam. Ranunadacece) . The po- 
tency of Aconite is such that 100 mg. possesses 
an activity equivalent to not less than 150 meg. 
of Reference Aconitine." N.F. The LP. requires 
Aconite Root to contain not less than 0.6 per cent 
of the alkaloids of aconite, of which not less than 
30 per cent consists of aconitine. 

LP. Aconiti Tuber; Aconite Root. Wolfsbane; Friar's 
Cap; Blue Rocket. Aconiti Tuber; Tubera Aconiti; Radix 
Aconiti. Fr. Aconit napel ; Coqueluchon. Ger. Eisenhut- 
knollen; Aconitknollen; Fuchswurz; Monchswurz; Wolfs- 
wurzel. It. Aconito. Sp. Tuberculo de aconito; Raiz de 
aconito. 

The name Aconite is derived, according to 
Pliny, from the ancient Black Sea port, Aconis. 
Some species of aconite was used by the ancient 
Chinese as well as by the hill tribes of India. 
While the physicians of Myddvai indicated the 
importance of aconite as a remedy during the 13th 
century, it was introduced into modern medicine 
by Storck, of Vienna, in 1763. The drug was ad- 
mitted into the London Pharmacopoeia in 1788 
and into the first U.S. P. The genus Aconitum is 
a relatively large one. there being some sixty well- 
defined species, nearly half of which have been 
used in medicine. The species which is official and 
recognized by nearly all the pharmacopoeias is 
Aconitum Napellus. It is indigenous to the moun- 
tainous regions of Middle Europe and is found 



Part I 



Aconite 



21 



growing in the Alps, Pyrenees and mountainous 
districts of Germany, Austria, Denmark, Sweden 
and Siberia, its range extending eastward to the 
Himalayas. It is not found in India, according to 
Dutt, the nearest approach to it there being 
A. soongariciim Stapf. The pure species occurs 
wild in North America as an escape from cultiva- 
tion. The most nearly related American plant is 
the variety delphinifolium Ser. which occurs from 
Alaska to British Columbia. Varieties and sub- 
species of A. Napellus are extensviely cultivated 
in temperate climates for their foliage and flowers. 
There are about twenty species of Aconitum 
which are indigenous to the mountainous regions 
of the United States, three of which occur in the 
eastern section, the remainder being distributed in 
the west, chiefly in the Rocky Mountains. 

Aconitum Napellus is a perennial herb attain- 
ing a height of 0.7 to 1.5 meters, with a fusiform 
to conical tuberous root, seldom exceeding 10 cm. 
in length and 2 cm. in thickness near the summit, 
brownish externally, whitish and fleshy within, 
and sending forth numerous long, thick, fleshy 
rootlets. When the plant is in full growth, there 
are usually two or three roots joined together by 
short shoots from axillary buds at the base of the 
stem, of which the oldest is dark brown, fusi- 
form, wrinkled, and supports the stem, while the 
youngest is of a light yellowish-brown color and 
conical shape and is destined to furnish the stem 
of the following year, the old root decaying. The 
stem is erect, round, smooth and leafy. The 
leaves are alternate, petiolate, with suborbicular, 
subcordate to broadly ovate, palmately 5- to 7- 
parted to divided blades, from two to four inches 
in diameter, deep green upon their upper surface, 
light green beneath, somewhat rigid, and more or 
less smooth and shining on both sides. Those on 
the lower part of the stem have long petioles and 
five or seven divisions; the upper, short petioles 
and three or five divisions. The divisions are 
wedge-form, with two or three lobes, which ex- 
tend nearly or quite to the middle. The lobes are 
cleft or toothed, and the lacinice or teeth are 
linear or linear-lanceolate and pointed. The flowers 
are of a dark violet-blue color, large and beauti- 
ful, and are borne at the summit of the stem 
upon a thick, simple, straight, erect, spike-like 
raceme, beneath which, in the cultivated plant, 
several smaller racemes arise from the axils of 
the upper leaves. There are 2 lanceolate bracts 
beneath each pediceled flower. The sepals are five, 
the upper helmet-shaped and beaked, nearly hemi- 
spherical, open or closed, the two lateral roundish 
and internally hairy, the two lower oblong-oval. 
They enclose 2 distinct, hammer-like, nectarif- 
erous petals which are covered by the hood of 
the posterior sepal. The stamens are numerous 
and hypogynous. The carpels are 3 to 4 with 
bilobed stigma. 

The fruit consists of 3 to 4 beaked follicles. 
The seeds are angular, wrinkled and very acrid. 
They rapidly lose their germinating power upon 
drying and storing and are for the greater part 
non-viable after a year. 

A number of subspecies, varieties and hybrids 
of A. Napellus are abundant in the alpine mead- 
ows and mountain forests of France, Switzerland, 



and Germany. Many of these are cultivated in 
the gardens of Europe, and have been introduced 
into this country as ornamental plants. All parts 
of the plants are acrid and poisonous. The leaves 
and flowering tops (Aconiti Folia) were formerly 
used but only the root is now official. The fresh 
leaves have a faint narcotic odor, most sensible 
when they are rubbed. Their taste is at first bitter 
and herbaceous, afterward burning and acrid, 
with a feeling of numbness and tingling, on the 
inside of the lips, tongue, and fauces, which is 
very durable, lasting sometimes many hours. The 
root is much more active than the leaves; an 
extract from the latter is said to have only one- 
twentieth of the strength of one made from the 
former. It should be gathered in autumn or winter 
after the leaves have fallen, and is not perfect 
until the second year. It has been mistakenly sub- 
stituted for horseradish root, as a condiment, 
with fatal effects. The studies of P. W. Squire 
seem to show that in the autumn the root is the 
most active. But the practical difficulty is that the 
root of A. paniculatum Lam. cannot be distin- 
guished by the ordinary collector from that of 
A. Napellus, except by taste; so that the custom 
of gathering the root about the flowering period 
is probably well founded. 

Aconite root is collected chiefly from plants, 
representing subspecies and varieties of A. Napel- 
lus, growing wild in the cool mountainous re- 
gions of Germany, Hungary, Switzerland, Spain 
and France. The tuberous roots are dug up in 
autumn, washed and carefully dried. The total 
imports of this drug into the United States in 
1952 were 4470 pounds, the suppliers being Italy 
and Spain. 

Commercial aconite root shows considerable 
variation and is usually a mixture of six or seven 
different kinds of tubers, as follows: 1. Single 
fleshy tubers which are smooth, light brown and 
full of starch. 2. Single tubers which are single, 
somewhat elongated fusiform, crowned with short 
stems, dark brown and longitudinally furrowed. 
3. Twin or triplet tubers, one of two of which 
(daughter tuber or tubers) being bud-crowned 
and the other (parent tuber) having a short stem 
at the summit. 4. Very small single tubers usually 
crowned with stems, the lower portion being acute 
or pointed. 5. Single tubers which are almost cyl- 
indrical, crowned with stems and either fleshy and 
nearly smooth or more or less shrunken and fur- 
rowed. 6. Dark brown resinous tubers. 7. Frag- 
ments of small and nearly filiform roots. 

The root has a feeble earthy odor. Though 
sweetish at first, it has afterward the same effect 
as the leaves upon the mouth and fauces. It 
shrinks much in drying, and becomes darker, but 
does not lose its acridity. 

Description. — "Unground Aconite occurs as a 
more or less conical root, from 4 to 10 cm. in 
length, and from 1 to 3.5 cm. in diameter at the 
crown; externally weak brown to moderate brown, 
smooth or longitudinally wrinkled, the upper end 
with a bud, or remains of bud-scales and stem- 
scar. The other portions possess numerous root- 
scars or short rootlets. The fracture is short, 
horny, or somewhat mealy; and the internal color 
is yellowish white through very pale orange to 



22 



Aconite 



Part I 



moderate yellowish brown. The bark is 1 to 2 mm. 
in thickness, and the cambium zone is usually 
5- to 8-angled. Aconite has a very slight odor and 
a sweet taste soon becoming acrid and developing 
a tingling sensation, followed by numbness." 
N.F.X. For histology see N.F.X. 

"Powdered Aconite is pale brown to weak yel- 
lowish orange. Starch grains are numerous, spheri- 
cal, somewhat planoconvex, single or 2- to 5-com- 
pound, the individual grains from 3 to 20 jx in 
diameter and frequently with a central cleft; 
vessels mostly with slit-like, simple pits, some- 
times with spiral or reticulate thickenings or with 
bordered pits; stone cells single, or in small 
groups, tabular, irregular, rectangular, or elon- 
gated in shape, from 100 to 400 n in length, walls 
strongly lignified and having simple pores. Also 
present are a few fragments of cells with brown- 
ish or yellowish walls; numerous fragments of 
parenchyma, the cells of which are filled with 
starch grains. Fibers from stems are few, very 
long, with lignified walls and marked by trans- 
verse or oblique, slit-like pits." N.F. 

Standards and Tests. — Aconite contains not 
more than 5 per cent of its stems and not more 
than 2 per cent of foreign organic matter, other 
than stems. N.F. 

Assay. — The N.F. directs that a tincture of 
the drug shall be prepared and assayed as directed 
under Aconite Tincture. The studies of Wolff e 
and Munch, described under Uses, cast doubt on 
the reliability of this bioassay as an evidence of 
the therapeutic value. Hoppe and Mollett (/. A. 
Ph. A., 1943, 32, 215), investigating the assay 
technic of Rowe in which white mice are used 
instead of guinea pigs, reported results having a 
standard error of approximately one per cent. A 
biological assay method for aconite tincture, em- 
ploying intravenous injections in mice and com- 
paring the LD50 doses of a reference standard 
aconitine solution and of dilutions of the tincture 
under test, has been developed by Barr and 
Nelson (/. A. Ph. A., 1949, 38, 518); the stand- 
ard error of a series of assays was found to be 
less than 2 per cent. A method based on the mini- 
mum dose necessary to produce emesis in pigeons 
has been suggested by Christensen and Nelson 
(/. A. Ph. A., 1940, 29, 97). 

The LP. assay for total alkaloids specifies ex- 
traction of the alkaloids by macerating the pow- 
dered drug with ether in the presence of ammonia; 
an aliquot portion of the ether solution is evapo- 
rated to dryness, and the residue titrated with 
0.1 N hydrochloric acid in the presence of methyl 
red and methylene blue as a mixed indicator. 
Each ml. of 0.1 N hydrochloric acid represents 
64.5 mg. of total alkaloids, calculated as aconitine. 
The determination of the proportion of aconitine 
is based on the residual titration, with 0.01 N 
sodium hydroxide and 0.01 N hydrochloric acid, 
of the benzoic acid obtained from this alkaloid 
upon alkaline hydrolysis. 

A chemical assay for aconite described by 
Bronkhorst (Pharm. Weekblad, 1935, 72, 1056) is 
based on hydrolysis of the alkaloids and estima- 
tion of the liberated acids. The method distin- 
guishes aconitine, benzoylaconine, and aconine. 
Baker and Jordan (/. A. Ph. A., 1936, 25, 291) 



suggested a method of analysis which takes ad- 
vantage of the difference in basic dissociation 
constants of aconitine and benzoylaconine, the 
latter being a stronger base. Other assay methods 
have been suggested by Schulze (Apoth.-Ztg., 
1933, 48, 94) and Neugebauer {Pharm. Zgt., 1933, 
78, 1077). 

Constituents. — Aconitum Napellus contains 
several alkaloids, though there seems to be some 
disagreement as to their identity. 

Aconitine is the most important alkaloid of the 
official drug. First isolated by Peschier in 1820, 
apparently in an impure form, it was first obtained 
in a crystalline state by Groves in 1860. There 
has been much discussion regarding the empirical 
formula for aconitine, but C34H47NO11 is now 
generally accepted; it is acetylbenzoylaconine. 

The alkaloid melts between 192° and 196° (with 
decomposition), is dextrorotatory, crystallizes in 
rhomic prisms, is soluble in chloroform and in 
benzene, less soluble in ether and in alcohol, 
and almost insoluble in water and in petroleum 
ether. It forms well-crystallized salts which are 
laevorotatory. 

Aconitine is precipitated from its solution by 
caustic alkalies, but not by ammonium carbonate, 
nor by potassium or sodium bicarbonate. It is 
easily hydrolyzed by acids or alkalies. In general, 
it has the incompatibilities characteristic of 
alkaloids. 

Many facts are known concerning the structure 
of aconitine, but it has not yet been fully eluci- 
dated. The molecule contains four methoxyl 
groups, three hydroxyl groups, and an ethylimino 
group. On hydrolysis by water under pressure, or 
by boiling with dilute acid, a molecule of acetic 
acid and one of benzoylaconine are produced; 
hydrolysis by alkalies releases both acetic and 
benzoic acids and yields aconine. Outstanding 
contributions to knowledge of the structure of 
aconitine have been made by Majima (Ann. 
Chem., 1936, 526, 116), Freudenberg (Ber., 1937, 
70B, 349) and Suginome (Ann. Chem., 1937, 533, 
172). For further information see Henry's Plant 
Alkaloids (1949), p. 674. 

Benzoylaconine, also known as benzaconine, 
isaconitine, and pier aconitine, accompanies aconi- 
tine in A. Napellus. Its empirical formula is 
C32H45NO10, and it is formed by the elimination 
of the acetyl group from aconitine. The base melts 
at 130°, is dextrorotatory, but forms crystalline 
salts which are levorotatory. Its toxicity is less 
than that of aconitine and it appears to differ 
somewhat in the type, as well as in the degree, of 
its physiological action. 

Aconine results from the hydrolysis of aconitine 
by alkali, but also occurs naturally in A. Napellus. 
It represents aconitine deprived of its acetyl and 
benzoyl groups, and has the formula C25H41NO9. 
It melts at 132°, is dextrorotatory, and likewise 
yields crystalline salts which are levorotatory. 
Aconine behaves as a cardiac stimulant and is 
antagonistic to aconitine. 

The alkaloid neopelline, C28H330s(OCH3)3- 
(NCH3).3H20, was isolated by Schulze and 
Berger (Arch. Pharm., 1924, 262, 553) from com- 
mercial "amorphous aconitine." It is amorphous; 
on alkaline hydrolysis acetic and benzoic acid 



Part I 



Aconite 



23 



are eliminated and neoline, C23H39NO6, is formed. 
The latter base is given the formula C24H11NO6 
by Freudenberg and Rogers (J.A.C.S., 1937, 59, 
2572) and said to be normally present in A. Napel- 
lus. The latter authors isolated the new alkaloid 
napelline, C22H33NO3, and found sparteine and 
/-ephedrine in amorphous acontine from A. Napel- 
lus. For an informative historical review on the 
chemistry of aconite see the article by Husa in 
A. Ph. A. Monograph No. 1, 1938, on Aconite. 

Alkaloids from other species of Aconite. 
— The alkaloids of Aconitum are mainly of two 
kinds: (1) aconitines, which are di-acyl esters of 
a series of polyhydric, amino-alcohols (aconities) 
and are highly toxic, and (2) the atisines, which are 
polyhydric amino-alcohols and of low toxicity. 

Some of the more toxic aconitines include 
pseudaconitine, from A. deinorrhizum and A. Bal- 
fourii (India) ; japaconitine, from A. uncinatum 
(Japan); indaconitine, from A. chasmanthum 
(India) ; and bikhaconitine, from A. spicatum 
(India). The group of less toxic alkaloids in- 
cludes atisine from A. heterophyllum and palm- 
atisine from A. palmatum. For a complete list of 
aconite alkaloids and their distribution among the 
species, see Henry {Plant Alkaloids, 1949). 

Many, probably all, species of aconite contain 
one or more alkaloids. While most of these alka- 
loids are poisonous, there is not sufficient evidence 
that their physiological action is the same as that 
of the official drug. It is therefore imperative 
that none of the other species be employed as a 
substitute for the official aconite; the fact that 
they may show a similar degree of toxicity on 
bio-assay provides no assurance of similarity of 
action, for the method of assaying aconite gives 
no indication of how it acts, only the amount re- 
quired to kill. 

For a description of other aconite species see 
U.S.D., 24th ed., p. 22. 

Uses. — Aconite is not widely used in the 
United States. The pharmacologic action of its 
chief alkaloid, aconitine, is stimulating and then 
depressing on the central and peripheral nervous 
system and resembles that of protoveratrine in 
some respects. On the cardiovascular system the 
action suggests that of quinidine. Topically, it is 
a counterirritant. 

History. — Aconite was well known to the an- 
cients as a powerful poison; it appears to have 
been used as an arrow poison early in Chinese 
history and perhaps also by the inhabitants of 
ancient Gaul. It is the basis of the legend of the 
"love poison" according to which the victim could 
be poisoned by sexual contact with a woman who 
had been fed aconite daily since infancy (Bull. 
Hist. Med., 1944, 15, 420). Although mentioned 
in the Meddygon Myddfai, published in Wales in 
the 12th century, it was introduced into regular 
medicine by Baron Storck of Vienna, whose ex- 
periments were published in the year 1762. Geiger 
(Annaien d. Pharm., 1834, 7, 269) described 
aconitine. 

Action. — Locally aconite is actively irritant 
and also a paralyzant to the peripheral sensory 
nerves. When applied to a mucous surface it pro- 
duces at first a burning, tingling sensation followed 
in a few minutes by a numbness. This sensation 



may even be perceptible after the systemic in- 
gestion of large doses. When administered inter- 
nally the first effect is generally a slowing of the 
pulse due to stimulation of the cardio-inhibitory 
centers, with consequent fall in the blood pressure 
and usually some slowing of respiration. With 
large doses, in the lower animals, the slow pulse 
suddenly becomes irregular and rapid with further 
fall of the blood pressure. These irregularities 
are apparently due to excitation of heteropic (mis- 
placed) impulses in the heart (Hueber and Lehr, 
Arch. exp. Path. Pharm., 1938, 189, 25). The 
heart becomes more and more irregular and even- 
tually passes into ventricular fibrillation (Tripod, 
Arch, internat. pharmacodyn. therap., 1951, 85, 
121), which is antagonized by a-fagarine or pro- 
caine in the isolated mammalian heart. According 
to Hueber and Lehr, magnesium antagonizes these 
cardiac irregularities. Aconite increases the toxic 
effects of calcium and digitalis on the heart. 

Wolffe and Munch (/. Pharmacol., 1934, 51, 
471) believe that the cardiac arrhythmia is due 
to the aconitine; they report that aconine will 
slow the pulse but not cause irregularities. There 
is apparently great variability in the potency of 
aconite; thus Wolffe (4. Ph. A. Monograph No. 1, 
1938) gave from 20 to 60 drops of an official tinc- 
ture to a number of patients with no apparent 
effect. Wolffe and Munch believe that the con- 
stituents of aconite that are not toxic to guinea 
pigs when tested by the official assay — chiefly 
aconine — may be the therapeutically desirable 
substances. Such constituents result from the 
hydrolysis of aconitine; hence such a preparation 
as aconite tincture may be of greater value when 
it has been allowed to stand long enough for the 
aconitine to have been hydrolyzed, which effect, 
paradoxically, is accompanied by diminished po- 
tency as measured by the guinea pig assay. This 
may account for the reports, from many practi- 
tioners, of good clinical results obtained from an 
old aconite preparation which had decomposed on 
standing. 

In the frog, large quantities of aconite produce 
a loss of reflex activity, which is apparently due to 
a paralysis of sensation as voluntary motion is 
preserved for some time later, although it too may 
eventually be abolished. The drug appears to 
affect both the sensory nerves and the receptive 
side of the spinal cord, although the latter is in- 
volved comparatively late in the poisoning. 

Therapeutic Use. — Aconite was formerly used 
in the treatment of febrile complaints ; any benefit 
it may have exerted is attributable to the lower- 
ing of blood pressure, which tends to promote 
sweating. It has been used to reduce overaction 
of the heart, especially in the absence of organic 
lesions, and occasionally to reduce high blood 
pressure. The variability of its potency and the 
closeness of its therapeutic and toxic closes have 
been responsible, in large measure, for its decline 
as a therapeutic agent. 

Aconite was formerly employed for its local 
irritant effect and anesthetic action in peripheral 
neuralgias; if used too freely for this purpose it 
may be absorbed through the skin in sufficient 
quantity to cause serious poisoning. It has been 
employed as a local anesthetic for the stomach in 



24 



Aconite 



Part I 



various types of vomiting or gastralgia but be- 
cause of its systemic effect is no longer thus used. 

For internal use the tincture (q. v.) is employed. 
As a febrifuge this was formerly given in a dose 
of 0.12 ml. every 10 minutes for an hour, then 
every hour until the fever subsided. For external 
application the fluidextract (N.F. IX) has been 
employed but an ointment was generally pre- 
ferred. This may be prepared by incorporating 
the fluidextract in 2 or 3 parts of lard or other 
base. Aconite and Chloroform Liniment, official 
in N.F. VIII, was prepared by mixing 45 ml. of 
aconite fluidextract, 80 ml. of alcohol, 125 ml. of 
chloroform, and 750 ml. of camphor and soap 
liniment; it was once a popular counterirritant 
liniment. The U.S. P. 1870 recognized a plaster of 
aconite. S 

Toxicology. — Aconite is a rapidly acting and 
powerful poison (Hartung, J.A.M.A., 1930, 95, 
1265). The symptoms produced by an overdose 
of it are sensations of warmth in the stomach, 
sometimes with nausea but usually without vomit- 
ing, slowing of the pulse and of the respiration; 
the skin is cool and moist, and there is profound 
prostration. As the poisoning progresses the res- 
pirations become more slow and shallow, the pulse 
becomes increasingly feeble, and toward the end 
rapid or very irregular. The only symptom of 
diagnostic importance is the characteristic numb- 
ness and tingling first felt in the lips and mouth, 
but later often also in the fingers. At times there 
is dimness of vision, the pupils may be either con- 
tracted or dilated, and occasionally delirium and 
stupor or convulsions may precede the fatal 
termination. Death, from cardio-respiratory fail- 
ure, occurs in Yz to 6 hours. As little as 5 ml. of 
the tincture may cause death. Poisoning has re- 
sulted from mistaking aconite for other plants, 
such a horse radish. 

In the treatment of aconite poisoning the pa- 
tient should be kept absolutely in a horizontal 
position, or with the feet higher than the head. 
If respiration is depressed, oxygen is indicated; 
artificial respiration may be needed. Gastric lavage 
is preferable to emetics as the latter cause strain 
upon the circulation. Hatcher (J.A.M.A., 1935, 
105, 502) recommended potassium permanganate 
as a chemical antidote. Hueber and Lehr (loc. 
cit.) and Mladoveanu (Arch, internat. pharm., 
1939, 63, 494) suggested parenteral use of mag- 
nesium sulfate to antagonize the cardiac effects 
in aconite poisoning. Hartung (Arch. exp. Path. 
Pharm., 1912, 69, 176) demonstrated experi- 
mentally the value of atropine. Other circulatory 
stimulants, such as strychnine or ammonia, may 
also be used. Body temperature should be main- 
tained by external application of heat. Bar- 
biturates may be used to control convulsions. 

Dose, of aconite root, 30 to 60 mg. (approxi- 
mately y 2 to 1 grain). A dose of 150 mg. in 24 
hours should seldom be exceeded. 

ACONITE TINCTURE. N.F. (LP.) 

[Tinctura Aconiti] 

"Aconite Tincture possesses a potency per ml. 
equivalent to 150 meg. of Reference Aconitine." 
N.F. The LP. Tincture of Aconite contains 0.045 



to 0.055 per cent w/v of total alkaloids, of which 
not less than 30 per cent consists of aconitine. 

Tincture of Aconite Root. Fr. Teinture d'aconit (racine). 
Ger. Eisenhuttinktur. It. Tintura di aconito. Sp. Tintura 
de aconito. 

Prepare the tincture from 100 Gm. of aconite, 
in fine powder, by Process P as modified for 
assayed tinctures (see under Tinctures), using a 
menstruum of 3 volumes of alcohol and 1 volume 
of water. Macerate the drug during 24 hours, 
then percolate at a rapid rate. Adjust the pH of 
the percolate to 3 ± 0.2, using hydrochloric acid; 
after assaying the liquid, dilute it to the required 
potency, including sufficient acid to maintain the 
specified pH. The official formula produces ap- 
proximately 1000 ml. of tincture. N.F. 

The adjustment of the reaction of this tincture 
is based on the finding of Swanson and Har- 
greaves (/. A. Ph. A., 1927, 16, 296), confirmed 
by Haag and Hawkins (J. A. Ph. A., 1930, 19, 
1284), that deterioration of the tincture (as meas- 
ured by the official assay — but see under Uses of 
Aconite) is in large measure prevented by adjust- 
ing it to a pH of 2.5 to 3.0. Hydrochloric acid was 
used for the acidification. 

Assay. — Opinion as to the relative merits of 
chemical and biological assay of aconite is di- 
vided, as is apparent from the number of methods 
of both types which have been proposed, some of 
which are described in the monograph on Aconite. 
The N.F. employs a biological method of assay. 

The first of the biological methods to have been 
used for testing aconite — in fact probably the 
oldest of all biological methods of standardizing — 
was that suggested by Dr. E. R. Squibb, this being 
based upon an observation of the characteristic 
effects of aconite on peripheral sensory nerve end- 
ings. The principle of the method consisted in 
determining the lowest dilution in which a given 
sample taken into the mouth of the experimenter 
produced the first perceptible degree of tingling 
in the tongue. The method was carried out as fol- 
lows : After rinsing the mouth with distilled water, 
4 ml. of an aqueous solution, representing one 
part of aconite root to 600 parts of water, was 
taken into the anterior part of the mouth and held 
there for one minute and then expelled. If the 
drug was of standard quality there resulted in a 
few minutes a characteristic sensation, too slight 
to properly be called tingling and yet closely allied 
to it. If, at the end of fifteen minutes, there was 
no distinct sensation the drug was considered to 
be below standard and stronger solutions were 
tested in the same manner. On the other hand, if 
it produced a sharp, distinct tingling it was 
stronger than normal and less concentrated solu- 
tions were tested. It is evident that personal sus- 
ceptibility played a considerable part in this 
method and it was necessary for the experimenter 
to standardize himself by determining his sensi- 
tiveness toward a sample of known potency. 
Even then, the test was hardly more than of 
qualitative value. 

The second method, adopted as the N.F. assay, 
is based on a comparison of the toxicity of a 
known dilution of the tincture with a standard 
solution of reference aconitine. Guinea pigs weigh- 



Part I 



Acriflavine 



25 



ing between 250 Gm. and 350 Gm., but not dif- 
fering by more than 50 Gm. in weight and all 
from the same colony of pigs, are used in the 
assay. Injections of the diluted aconite tincture, 
and of the reference aconitine solution, are in- 
jected under the skin of the abdomen of the guinea 
pigs; the experiment consists in determining the 
dose of each preparation which will kill not more 
than 7 and not less than 3 animals of groups of 10 
animals used for each solution, within 6 hours. 
When the respective mortalities from the refer- 
ence standard and the preparation being assayed 
differ by not more than 2 animals the doses may 
be considered equivalent and a comparison of 
relative potencies of the preparations made. The 
N.F. states, however, that "owing to many vari- 
able factors in this assay which make it difficult 
for different operators to obtain identical results, 
the evidence of potency within 20 per cent above 
or 20 per cent below the standard is accepted." 
For other methods of assay see under Aconite. 

Alcohol Content. — From 65 to 70 per cent by 
volume of C2H5OH. N.F. 

There was formerly employed in the United 
States, and at one time recognized by the N.F., 
a preparation known as Fleming's Tincture of 
Aconite, which represented 70 per cent of aco- 
nite root. 

Uses. — For discussion of uses of aconite, in- 
cluding the tincture, see the preceding monograph. 
At one time aconite tincture was a popular prep- 
aration but the variation in its potency and the 
uncertainty of its action have materially limited 
its use. 

Dose, 0.3 to 1 ml. (approximately 5 to 15 
minims). 

Storage. — Preserve "in tight, light-resistant 
containers and avoid exposure to direct sunlight or 
to excessive heat." N.F. 



ACONITINE. 

Aconitinum 



LP. 



The LP. defines aconitine as acetylbenzoylaco- 
nine, and requires it to contain not less than 99.0 
per cent of C34H47NO11. 

Aconitine is usually obtained from Aconitum 
Napellus. In one of the several extraction proce- 
dures which may be used the drug is exhausted 
with methanol containing 1 per cent of tartaric 
acid. The extract is concentrated, diluted with 
several volumes of water, and treated with pe- 
troleum ether to remove fatty impurities. The 
aqueous solution is then alkalinized with ammonia 
and the total alkaloids extracted with ethyl or 
isopropyl ether, or with benzene or toluene. From 
this solution the alkaloids are extracted with small 
volumes of 36 per cent hydrobromic acid; on 
cooling this solution aconitine hydrobromide 
crystallizes, particularly if some ammonium bro- 
mide is added. Instead of using hydrobromic acid, 
a 10 per cent solution of hydrochloric acid may 
be used; to this is added sodium iodide to pre- 
cipitate the aconitine as hydriodide. 

For information concerning chemical charac- 
teristics of aconitine see Constituents, under 
Aconite. 

Description. — Aconitine occurs in colorless 



crystals or as a white, crystalline powder; it is 
odorless; a sensation of tingling, free from bit- 
terness, is produced by as small a quantity as 
6 micrograms placed on the tongue (the alkaloid 
is extremely poisonous!). Aconitine dissolves in 
about 4500 parts of water, in about 40 parts of 
ethanol (90 per cent), in about 70 parts of ether, 
in about 2800 parts of petroleum ether, and in 
about 10 parts of benzene; it is very soluble in 
chloroform. It melts between 192°and 196°, with 
decomposition. LP. 

Standards and Tests. — Identification. — An 
aqueous solution, made slightly acid with acetic 
acid, yields a colorless, well-crystallized pre- 
cipitate upon addition of potassium iodide T.S. 
Pseudoaconitine. — A yellow residue is produced 
on moistening aconitine with fuming nitric acid 
and evaporating to dryness on a water bath; on 
moistening the residue with a freshly-prepared 
10 per cent (w/v) solution of potassium hydrox- 
ide in alcohol no purple color is produced. LP. 

Assay.— About 300 mg. of aconitine is dis- 
solved in 10 ml. of 0.1 N hydrochloric acid and 
the excess acid is titrated with 0.1 A 7 sodium 
hydroxide, using methyl red as indicator. Each 
ml. of 0.1 N hydrochloric acid represents 64.6 mg. 
of C34H47NO11. LP. 

Uses. — While aconitine was long ago deleted 
from both the U.S. P. and the B.P. it maintains a 
degree of popularity in some European and South 
American countries for which reason, apparently, 
it is included in the LP. 

In neuralgia aconitine is applied externally in 
the form of a 2 per cent ointment; the alkaloid 
is dissolved in 8 parts of oleic acid and this solu- 
tion is incorporated in an ointment base, gener- 
ally lard. A 2 per cent solution of aconitine in 
oleic acid is employed for the same purpose. 
Care must be observed in applying these prepara- 
tions to avoid contact with mucous membranes 
or raw skin. 

Aconitine is sometimes given internally for its 
diaphoretic and depressant effect, but such use 
may be dangerous because of the powerful cardiac 
action of the drug (see Uses, under Aconite). 

The average dose of aconitine is 0.1 mg. (ap- 
proximately %40 grain) ; doses up to 0.3 mg. (ap- 
proximately %oo grain) are sometimes given, 
which in very rare instances have been cau- 
tiously increased to a single dose of 1 mg. (ap- 
proximately Vm grain). 

Storage. — Preserve in a well-closed container, 
protected from light. LP. 

ACRIFLAVINE. N.F. 

Acriflavine Base, Neutral Acriflavine, [Acriflavina] 

"Acriflavine is a mixture of 3,6-diamino-10- 
methylacridinium chloride and 3,6-diaminoacri- 
dine containing, when dried at 105° for 2 hours, 
not less than 13.3 per cent and not more than 15.8 
per cent of CI." N.F. 

Trypaflavine {Delta) ; Gonacrine; Neutroflavine; Eufla- 
vine. Acridinum Hydrochloricum. Fr. Chlorhydrate de 
diaminoacridine. 

Derivatives of acridine have long been em- 
ployed in the dye industry, "acridine yellow" 
having been first marketed in 1889. In 1896 
Tappeiner, because of the similarity in the struc- 



26 



Acriflavine 



Part I 



ture of acridine and quinoline, made some experi- 
ments on the antimalarial activity of acridine de- 
rivatives, which, however, were not encouraging. 
It was not until 1912 when Benda introduced 
diamino-acridinium-methyl-chloride, which Ehrlich 
(Ber., 1913, 46, 1931) showed to be definitely 
trypanocidal, that acridine dyes became of medici- 
nal importance. Since then a number of com- 
pounds chemically related to acriflavine have been 
used. 

Acriflavine is sometimes called acriflavine base 
or neutral acriflavine but this designation is hardlv 
correct, for Collins (/. A. Ph. A., 1929, 17, 659) 
showed that in aqueous solution the pH is be- 
tween 3 and 5 ; that is, it is distinctly acid. 

The preparation of acriflavine involves a series 
of reactions which may be summarized as fol- 
lows: Aniline and formaldehyde undergo inter- 
action to form 4,4-diaminodiphenylmethane; this 
is nitrated to 2,2'-dinitro-4,4'-diaminodiphenyl- 
methane and the latter is reduced with tin and 
hydrochloric acid to form the stannichloride of 
3,6-diaminoacridine; after acetylation of the 
amino groups, the nitrogen atom in the ring is 
methylated by the use of methyl ^-toluenesulfon- 
ate and the acetyl groups are subsequently re- 
moved by heating with hydrochloric acid. 

The preparation of pure acriflavine from com- 
mercial samples containing much diaminoacridine 
may be achieved by treatment with sodium hy- 
droxide and subsequent recrystallization. 

Description. — "Acriflavine occurs as a deep 
orange, odorless, granular powder. Solutions of 
Acriflavine are reddish orange in color and become 
fluorescent on dilution. One Gm. of Acriflavine dis- 
solves in about 3 ml. of water. It is incompletely 
soluble in alcohol, is nearly insoluble in ether, in 
chloroform, and in fixed oils." N.F. 

Standards and Tests. — Identification. — (1) 
On adding a few drops of hydrochloric acid to a 
solution of acriflavine that has been diluted until 
it just exhibits fluorescence the fluorescence dis- 
appears but reappears partially on dilution with 
distilled water. (2) A reddish-orange crystalline 
precipitate is formed on adding 2 drops of sulfuric 
acid to 1 ml. of a 1 in 250 aqueous solution of 
acriflavine. (3) No effervescence results on mix- 
ing equal volumes of a solution of acriflavine with 
a saturated solution of sodium bicarbonate (acri- 
flavine hydrochloride does produce an efferves- 
cence). Loss on drying. — Not more than 8 per 
cent, when dried for 2 hours at 105°. Residue on 
ignition. — Not over 35 mg. from 1 Gm. of acri- 
flavine ignited with 1 ml. of sulfuric acid. Water- 
insoluble substances. — Not over 0.5 per cent. 
Arsenic. — 200 mg. of acriflavine meets the re- 
quirements of the test for arsenic, corresponding 
to a limit of 10 parts per million. N.F. 

Assay for Chlorine. — A sample of about 250 
mg. of acriflavine, previously dried for 2 hours 
at 105°, is dissolved in water and heated with a 
solution containing silver nitrate, sulfuric acid 
and potassium permanganate to precipitate silver 
chloride while oxidizing the remainder of the acri- 
flavine molecule. The precipitate is filtered on a 
Gooch crucible, washed first with 1 in 3 nitric 
acid, then with distilled water, and dried to con- 



stant weight at 105°. Each Gm. of silver chloride 
represents 247.4 mg. of CI. N.F. 

For an account of therapeutic properties see 
under Acriflavine Hydrochloride. For intravenous 
injection the "acriflavine base" is preferable to 
the hydrochloride because of its lower acidity. 
The beginning dose which has been used is about 
100 mg. (approximately \ l /i grains) administered 
intravenously once a day, which may be cautiously 
increased, bearing always in mind the possible 
injurious effects on the liver. 

Storage. — Preserve "in tight containers." N.F. 

ACRIFLAVINE HYDROCHLORIDE. 

N.F. 

[Acriflavinae Hydrochloridum] 

"Acriflavine Hydrochloride is a mixture of the 
hydrochlorides of 3,6-diamino-10-methylacridin- 
ium chloride and 3,6-diaminoacridine, yielding, 
when dried for 1 hour at 105°, not less than 23 
per cent and not more than 24.5 per cent of CI." 
N.F. 

Acid Acriflavine; Acid Trypaflavine. 

The two NHs groups of acriflavine are capable 
of reacting with acids to form salts; thus, acri- 
flavine may form a monohydrochloride and a 
dihydrochloride. The official substance is the 
monohydrochloride. For information concerning 
the chemistry of acriflavine see the preceding 
monograph. 

Description. — "Acriflavine Hydrochloride oc- 
curs as a strong reddish brown, odorless, crystal- 
line powder. Solutions of Acriflavine Hydrochlo- 
ride are dark red in color and become fluorescent 
on dilution. One Gm. of Acriflavine Hydrochlo- 
ride dissolves in about 3 ml. of water, and is 
soluble in alcohol. It is nearly insoluble in ether, 
in chloroform, in liquid petrolatum, and in fixed 
or volatile oils. One Gm. of Acriflavine Hydro- 
chloride, dissolved in 50 ml. of warm distilled 
water, forms a clear solution, which remains clear 
and free from sediment on standing in the dark 
for 24 hours. Dissolve 200 mg. of Acriflavine 
Hydrochloride in 100 ml. of isotonic sodium chlo- 
ride solution: a clear solution is obtained, which 
remains clear and free from sediment on standing 
in the dark for 24 hours." N.F. The solubility of 
acriflavine hydrochloride varies somewhat with 
the proportions of its components, hence commer- 
cial samples do not always have identical solu- 
bilities. It is of interest that the mixture is more 
soluble than either component. 

Standards and Tests. — Identification. — Acri- 
flavine hydrochloride responds to the tests pre- 
scribed for acriflavine except that its solutions are 
dark red, and in test (3) an effervescence is pro- 
duced. Loss on drying. — Not over 7 per cent on 
drying for 1 hour at 105°. Residue on ignition. — 
Not over 10 mg. from 1 Gm. of acriflavine hydro- 
chloride with 1 ml. of sulfuric acid. Arsenic. — The 
requirement is the same as for acriflavine. N.F. 

Assay. — The N.F. directs that the assay be 
performed as specified under Acriflavine. 

Incompatibilities. — Acriflavine and its hydro- 
chloride are incompatible with solutions contain- 



Part I 



Adrenal Cortex Injection 27 



ing chlorine, phenol or mercuric chloride. With 
alkalies and with silver nitrate a precipitate is 
produced. While acriflavine hydrochloride is com- 
patible with normal salt solution for immediate 
use, precipitation occurs upon standing. Salt solu- 
tions stronger than 5 per cent produce a pre- 
cipitate immediately. Solutions of acriflavine 
hydrochloride are acid and may give rise to in- 
compatibilities for this reason. 

Uses. — The most important use of acriflavine 
is as a wound antiseptic. This antiseptic is an out- 
come of investigations, commencing with Ehrlich, 
to find a dye which will stain the microorganism, 
and thereby injure it, without staining the tissues 
of the host; thus it would have low toxicity to 
the host. In addition to acriflavine, the related 
substances aminacrine hydrochloride and pro- 
flavine hemisulfate are official in the B.P. 

Acriflavine is not an extremely powerful bac- 
tericide but it is a very active bacteriostatic sub- 
stance. It is usually employed in strengths of 
about 1 in 1000 in physiological saline solution. 
Browning, who advocated use of acriflavine as a 
surface antiseptic in 1917, reviewed the more re- 
cent status of this drug (Brit. M. J., 1943, 1, 341) 
as follows: it is bacteriostatic against important 
pyogenic bacteria; serum does not diminish its 
action but blood and pus do ; its systemic toxicity 
is low (100 mg. intravenously every other day 
for 10 doses is well tolerated) and it is not ab- 
sorbed sufficiently from wounds to be toxic; in 
the 1:1000 solution concentration it causes little 
tissue damage; phagocytosis is but little dis- 
turbed; skin idiosyncrasy is rare; it is able to 
destroy infection in a fresh wound before sig- 
nificant invasion occurs; established infection is 
cleaned up better by the 1 :1000 solution than by 
the local use of the sulfonamide drugs; it does 
not delay healing; in serum a concentration of 1 
in 200,000 sterilizes either Staphylococcus aureus 
or Bacillus coli within 24 hours and is active 
against Streptococcus pyogenes in even higher di- 
lutions; Bacillus pyocyaneus, proteus and some 
strains of coli are highly resistant to acriflavine. 

Extensive comparisons of the bacteriostatic and 
bactericidal action of acriflavine with other acri- 
dine antiseptics have been published (/. Pharma- 
col., 1944, 80, 217; /. Lab. Clin. Med., 1944, 29, 
134 and 1177 and 1945, 30, 145). Martin and 
Fisher (J. Lab. Clin. Med., 1944, 29, 383) re- 
ported that the bacteriostatic action of the acri- 
dine antiseptics is due to inhibition of adenine- 
containing factors such as coenzymes I and II, 
which are essential to bacteria (see also O'Connor, 
Brit. J. Exp. Path., 1951, 32, 547). Garrod (Brit. 
M. /., April 4, 1931) pointed out that it is not ad- 
visable to apply it on cotton dressings because the 
affinity for cotton reduces its antiseptic action. 

Acriflavine has been employed as an injection 
in gonorrheal urethritis in 1 in 1000 concentration 
and as a bladder irrigation in 1 in 5000 concentra- 
tion. It has also been used for sterilizing the skin 
as a 5 per cent solution in alcohol, acetone and 
water (see Tinker and Sutton, J. A.M. A., 1926, 
87, 1347 and Berry, Pharm. J., 1937, 139, 541, 
571). Roxburgh (Pract., 1941, 146, 289) advo- 
cated treatment of impetigo by removal of the 



crusts and painting of the raw area with 1 in 1000 
acriflavine. 

Acriflavine has been given by mouth as a uri- 
nary antiseptic in doses of 200 mg. daily; for best 
effect the urine must be kept alkaline. Assinder 
(Lancet, 1936, 1, 304) reported great variation in 
the toxicity of different samples. 

According to Crittenden (/. Pharmacol., 1932, 
44, 423) small doses cause a moderate transient 
rise in blood pressure, while large doses cause a 
fall in blood pressure with a slowing of the heart. 
He also found considerable difference in the 
toxicity of individual samples. Heathcoat and 
Urquhart (/. Pharmacol., 1930, 38, 145) reported 
the acutely fatal intravenous dose for animals as 
about 25 mg. per Kg. but that repeated injections 
of less than half of this quantity eventually 
proved fatal, with evidence of injurious effects on 
the fiver and the kidney (see also Levrat, Compt. 
rend. soc. biol., 1933, 114, 60). 

Prior to the availability of the sulfonamides 
and antibiotics, a 2 per cent aqueous solution was 
used intravenously in doses of 10 to 15 ml., slowly, 
or diluted with 250 ml. of isotonic sodium chlo- 
ride solution, at intervals of 1 or 3 days, in the 
treatment of brucellosis (Debono, Brit. M. J., 
199, 1, 326), tularemia (Loria, Am. J. Med. Sc, 
1941, 202, 803), psittacosis (Koch, Deutsche 
med. Wchnschr., 1940, 32, 877), blastomycosis 
(Pupo, J.A.M.A., 1928, 91, 1733), trypanosomi- 
asis (Hawking, Ann. Prop. Med., 1938, 32, 367), 
leishmaniasis (Senekji, J. Path. Bact., 1940, 50, 
171), and schistosomiasis (Fisher, Lancet, 1934, 
1, 897 and 2, 1017); however, Khali and Salah 
(Lancet, 1934, 2, 862) reported it to be ineffec- 
tive in the last-named condition, [v] 

The N.F. states that acriflavine and its hydro- 
chloride are used locally in 1:1000 solution, and 
for irrigation in 1:10,000 to 1:1000 solution. For 
intravenous dosage see under Acriflavine. 

To remove stains of acriflavine or its hydro- 
chloride from the hands it is recommended that a 
little dilute sulfurous acid be applied, followed by 
dilute hydrochloric acid, then washed with water. 

Storage. — Preserve "in tight containers." N.F. 

ADRENAL CORTEX INJECTION. 
U.S.P. 

"Adrenal Cortex Injection is a sterile solution 
in alcohol and water for injection containing a 
mixture of the endocrine principles derived from 
the cortex of adrenal glands of healthy domestic 
animals used for food by man. Each ml. of Ad- 
renal Cortex Injection exhibits a biological activity 
equivalent to that of 100 micrograms of U.S.P. 
Hydrocortisone Acetate Reference Standard. It 
contains a suitable antibacterial agent." U.S.P. 

The adrenal glands, also known as suprarenal 
glands and suprarenal bodies and suprarenal cap- 
sules, are small glandular bodies found in all 
mammals, being located immediately above the 
kidney. In man they weigh about 6 or 7 Gm. They 
consist of two distinct portions: an outer layer, 
known as the cortex, varying in thickness from 
0.25 to 1.2 mm., and an inner, medullary portion. 
It has long been recognized that extirpation of 



28 Adrenal Cortex Injection 



Part I 



these glands in lower animals is almost invariably 
fatal within a week or two. 

The physiologically important principle of the 
medullary portion of adrenal glands is epinephrine 
(for information see under Epinephrine), while 
the cortex contains a large number of compounds, 
several of which have pronounced physiological 
activity. Fractionation of pure extracts of adrenal 
cortex (about 9 Gm. of extract is obtained from 
1000 pounds of adrenal glands) by Kendall, 
Reichstein, Wintersteiner, Kuizenga, Cartland 
and others has led to the isolation of 28 crystalline 
steroids and a residual amorphous fraction from 
which latter there was recently isolated still an- 
other crystalline steroid. At least seven of the 
crystalline compounds (including the one most 
recently isolated) have activity which is charac- 
teristic of the adrenal cortex. Several androgens 
and estrogens are included in the group of hor- 
mones which have been isolated but since their 
activity is not specific for the adrenal gland they 
are not of primary interest in any discussion of 
characteristic adrenal cortex hormones. The seven 
hormones of interest in this connection are: 11- 
desoxycorticosterone, the one which possesses the 
greatest activity in maintaining life in adrenalec- 
tomized animals, official in the U.S. P. as Desoxy- 
corticosterone Acetate; 11-dehydrocorticosterone, 
known also as Kendall's Compound A; corticos- 
terone, known also as Kendall's Compound B and 
Reichstein's Substance H; 17-hydroxy-l 1-dehy- 
drocorticosterone, known also as Kendall's Com- 
pound E, Wintersteiner' s Compound F and Reich- 
stein's Substance Fa, and official in the U.S. P. as 
the acetate under the title Cortisone Acetate; 17- 
hydroxycorticosterone, known also as Kendall's 
Compound F and Reichstein's Substance M, and 
official in the U.S. P. as Hydrocortisone and also, 
in the form of the acetate, as Hydrocortisone 
Acetate; 17 - hydroxy - 11 - desoxycorticosterone, 
known also as Reichstein's Substance S; the new 
crystalline hormone, with high activity in the 
control of mineral metabolism, first called elec- 
trocortin but renamed aldosterone after its chem- 
ical structure was established to be llP,21-dihy- 
droxy-3,20-diketo-4-pregnene-18-al (for details of 
isolation and characterization see Harman et al., 
J.A.C.S., 1954, 76, 5035; for other information 
see under Desoxycorticosterone Acetate). 

For a summary of the procedure for preparing 
active extracts of the adrenal cortex, and for their 
fractionation, as well as the chemistry of the in- 
dividual compounds, see Kuizenga in the A.A.A.S. 
volume on The Chemistry and Physiology of 
Hormones (1944). Manufacturing details may be 
found also in U. S. Patents 2,053,549 (1936) and 
2,096.342 (1937). 

Under the title Suprarenal the dried, partially 
defatted and powdered suprarenal gland of cattle, 
sheep, or swine, representing approximately 6 
parts by weight of fresh glands, was long offi- 
cially recognized, most recently in N.F. VIII. For 
information concerning it see U.S.D., 24th ed., 
p. 1171. 

Description. — "Adrenal Cortex Injection is 
a clear, colorless, or faintly colored solution." 
U.S.P. 

Standards and Tests.— pH— The pH of the 



injection is between 4.0 and 6.0. Pyrogen. — The 
injection meets the requirements of the official 
pyrogen test, the test dose being 1 ml. per Kg. 
Other requirements. — The injection meets the re- 
quirements for Injections. Pressor substances. — 
The injection exhibits a pressor activity equivalent 
to not more than 0.2 mg. of epinephrine in each 
100 ml. U.S.P. 

Assay. — The assay is based on measurement of 
the ability of the adrenal cortex injection under 
test to promote deposition of glycogen in the liver 
of adrenalectomized rats; in the assay the liver 
glycogen content is determined through interac- 
tion of glucose obtained from the glycogen with 
alkaline cupric sulfate T.S., followed by estima- 
tion of the excess of cupric ion by release of 
iodine and titration with sodium thiosulfate volu- 
metric solution. Quantitative evaluation of the 
effect is obtained by comparison with the effect 
produced by Hydrocortisone Acetate Reference 
Standard under similar experimental conditions. 
U.S.P. 

Uses. — The chief indication for suprarenal ex- 
tract is in the management of acute crises in 
Addison's disease; maintenance therapy is simpler, 
more effective, and less costly when cortisone or 
hydrocortisone, desoxycorticosterone and sodium 
chloride are used. Since the adrenal extract is 
more efficient in the muscle work test than any 
combination of isolated adrenal steroids it is pos- 
sible that it contains unidentified factors which 
may have therapeutic value in various conditions. 
On the other hand Thorn et al. (New Eng. J. 
Med., 1953, 248, 420) found that intravenous 
injections of hydrocortisone produce rapid meta- 
bolic effects of maximal intensity and believe that 
this dosage form will eventually replace adrenal 
extract for use in the correction of acute adrenal 
insufficiency. The characteristics and treatment of 
adrenal insufficiency are discussed under Desoxy- 
corticosterone Acetate, while hyperfunction of 
the adrenal gland is discussed under Cortisone 
Acetate. 

History. — Thomas Addison described, in 1855, 
the syndrome of adrenal insufficiency which is 
commonly referred to as Addison's disease. In 
1856 Brown-Sequard reported his experimental 
demonstration, in animals, that the adrenal gland 
is essential for life. Osier's report (Internat. Med. 
Mag., 1896, 5, 3) that oral administration of a 
glycerin extract of fresh hog adrenal glands pro- 
duced marked improvement in a patient with 
Addison's disease was obscured and forgotten 
when the vasopressor action of adrenal extracts 
was recognized by Oliver and Schafer in 1895 
(see Brit. M. J., 1901, 1, 1009) and by the failure 
of epinephrine to improve the patient with adre- 
nal insufficiency. That it is the cortex of the 
adrenal gland which is essential for life was dem- 
onstrated by Houssay and Lewis (Am. J. Physiol., 
1923, 66, 512) and others. About three decades 
after Osier's report. Hartman et al. (Proc. S. Exp. 
Biol. Med., 1927, 25, 69), and Rogoff and Stewart 
(Science, 1927, 66, 327) reported prolongation of 
life in adrenalectomized animals following admin- 
istration of an extract of the adrenal cortex. 
Swingle and Pfiffner (ibid., 1930, 71, 321) pre- 
pared a potent extract which proved to be clini- 



Part I 



Adrenal Cortex Injection 29 



cally effective (see Rowntree, J. A.M. A., 1940, 
114, 2526) and which came into use under the 
name Eschatin (Parke, Davis); Hartman and 
Brownell (Proc. S. Exp. Biol. Med., 1930, 27, 
938) simultaneously produced a potent extract 
which was also useful in patients. In the light of 
later knowledge of the activity of adrenal cortical 
steroids, these extracts were weak, costly, and 
available in insufficient quatnity for many thera- 
peutic requirements. Improved extraction meth- 
ods were reported by Kuizenga et al. (J. Biol. 
Chem., 1943, 147, 561). Currently available ex- 
tracts are standardized on adrenalectomized rats 
to have a liver glycogen deposition activity cor- 
responding to that of 0.1 mg. of hydrocortisone 
acetate per ml. (see U.S. P. requirement and assay 
above j. Extracts have also been standardized using 
adrenalectomized dogs (Cartland and Kuizenga, 
Am. J. Physiol., 1936, 117, 678); a dog unit is 
the amount of material per Kg. of body weight 
required daily to maintain the animal in good 
condition with a normal blood non-protein nitro- 
gen level. Dog units may be transposed in terms 
of hydrocortisone on the assumption that 50 dog 
units are equivalent to 0.1 mg. of hydrocortisone. 
The most active extract developed, Lipo-Adrenal 
Cortex, Sterile Solution (Upjohn), contains in 1 
ml. the activity of 1 mg. of hydrocortisone. 

Action. — Physiologically, the adrenal cortex 
hormones, which are present in extracts, fall into 
two categories: 11-desoxycorticosterone, 17-hy- 
droxy-11-desoxycorticosterone and, apparently, 
aldosterone (electrocortin) are concerned chiefly 
with electrolyte and fluid balance; corticosterone, 
1 1-dehydrocorticosterone, 1 7-hydroxycorticoster- 
one (hydrocortisone), and 17-hydroxy-l 1-dehy- 
drocorticosterone (cortisone) are more active in 
carbohydrate and protein metabolism. The loss of 
sodium seems to be related to the inability of 
renal tubules to reabsorb sodium; this is perhaps 
the most serious defect in adrenal insufficiency 
and is corrected by adrenal cortical extracts 
(Thorn et al., Endocrinology, 1937, 21, 213). 
The hormones of the second category, which have 
an oxygen or a hydroxyl group in the 11 position, 
seem to increase conversion of protein to carbo- 
hydrate (gluconeogenesis) and utilization of car- 
bohydrate in the liver but to decrease peripheral 
utilization of glucose (Long, ibid., 1942, 30, 870); 
this antagonizes the action of insulin which tends 
to promote protein synthesis and increase periph- 
eral utilization of carbohydrate. Adrenal cortex 
extracts correct the abnormality in carbohydrate 
metabolism (Hartman et al., J.A.M.A., 1932, 98, 
788). The decreased ability of muscles to work is 
perhaps related to this defect in protein and car- 
bohydrate metabolism (Lewis et al., Endocrinol- 
ogy, 1940, 27, 971; Ingle, ibid., 1942, 31, 419) 
but these metabolic effects are inadequately under- 
stood and a complex interaction of pituitary, 
thyroid, pancreas and other organs is probably 
involved. Adrenal hormones also maintain normal 
capillary permeability. The bronze pigmentation 
of the skin of the patient with Addison's disease 
becomes lighter when adrenal cortex extract is 
employed (Hartman et al, J.A.M.A., 1932, 99, 
1478). Resistance to infection and stress of all 
types is related to adrenal function. Increase in 



blood lymphocytes (White and Dougherty, Endo- 
crinology, 1945, 36, 207) and decrease in serum 
gamma globulin content (immune bodies) in defi- 
ciency states are corrected by the steroid hor- 
mones. 

For therapeutic purposes both groups of adre- 
nal steroid hormones are needed, and are provided 
by the available extracts. However, very large 
doses are necessary, and the cost is sometimes 
prohibitive. The less costly synthetic compound 
desoxycorticosterone acetate has made it possible 
to control the disturbance in water and electrolyte 
metabolism, though this compound does not pre- 
vent hypoglycemia, particularly in association 
with infections, gastrointestinal disturbances or 
other states of stress. The present availability of 
cortisone and hydrocortisone provides an ample 
supply of glycocorticoid activity. 

Therapeutic Uses. — The management of 
adrenal insufficiency, as presented by Thorn 
(J.A.M.A., 1944, 125, 10) involves several fac- 
tors (see also under Desoxycorticosterone Ace- 
tate, Cortisone Acetate, and Hydrocortisone Ace- 
tate). In the acute crisis, bed rest is essential. 
Water and salt are greatly needed, and up to 4 
liters of isotonic sodium chloride solution should 
be given intravenously during the first 24 hours. 
Dextrose is also needed, being given intravenously 
in 5 per cent solution in water for injection or 
isotonic sodium chloride solution but it must be 
administered with caution because fatalities have 
resulted from rapid and unintelligent administra- 
tion. Adrenal cortex extract is started at once in 
a dose of 30 to 50 ml. intravenously and, simul- 
taneously, 10 ml. intramuscularly; the latter is 
repeated every hour until the patient reacts from 
the crisis (usually about 12 hours), then every 2 
to 3 hours during the second 12-hour period, and 
subsequently every 3 to 6 hours until the patient 
is afebrile and well. In addition to adrenal cortex 
injection, 20 mg. of desoxycorticosterone acetate 
in oil should be given intramuscularly immedi- 
ately, followed by a dose of 5 to 10 mg. daily until 
the patient is well. If the systolic blood pressure 
is less than 90 mm. of mercury, epinephrine or 
ephedrine should be used hypodermically. If the 
blood pressure remains low, whole blood or plasma 
is indicated intravenously. Oral fluids may be 
permitted as tolerated. Morphine is contraindi- 
cated. 

In chronic states of deficiency or after recovery 
from an acute crisis, infection, fasting and exces- 
sive stress and strain must be avoided. A diet 
high in sodium chloride but low in potassium is 
indicated; from 3 to 10 Gm. of sodium chloride, 
as enteric-coated tablets, should be administered 
daily. Although some mild cases may be kept in 
a state of health with the high sodium diet only, 
the majority of patients will require some form 
of adrenal cortical hormone. Desoxycorticosterone 
acetate, which regulates only the water and salt 
metabolism, may suffice. It has the important 
virtue of being cheaper therapy; implantation of 
pellets (see under Desoxycorticosterone Acetate) 
about once a year is often effective and avoids 
repeated injections. Adrenal cortical extract, 
which provides the carbohydrate as well as the 
water and salt regulating substances, may be 



30 



Adrenal Cortex Injection 



Part I 



required in doses as high as 15 to 20 ml. intra- 
muscularly daily. Cortisone acetate by mouth and 
extra salt in the diet will control many cases 
without the necessity for injections of desoxycor- 
ticosterone or adrenal cortex extract. Therapy is 
guided by the disappearance of clinical symptoms, 
weight gain and the maintenance of a normal 
blood pressure. Infection increases the amount of 
cortical hormone needed. 

In addition to the treatment of Addison's dis- 
ease, the adrenal steroid hormones have been 
employed with benefit in the management of the 
shock of severe thermal burns (Scudder and 
Elliott, South. Med. Surg., 1942, 104, 651) and 
of traumatic or surgical shock (Helfrich et al., 
Am. J. Surg., 1942, 55, 410). However, Rhoads 
et al. {Ann. Surg., 1943, 118, 982) reversed their 
preliminary impression of the value of these 
hormones in the shock due to burns. Likewise, 
Koster and Kagman {Arch. Surg., 1941, 45, 2 724) 
denied any benefit, in surgical shock. Some of this 
controversy doubtless arose from the use of the 
relatively weak extracts which were available. In 
the Waterhouse-Friderichsen syndrome (acute 
adrenal insufficiency in meningococcal infections 
which is often due to hemorrhage into the adre- 
nals), early diagnosis and vigorous treatment for 
the Addisonian crisis may alter the otherwise 
hopeless prognosis (Weinberg and McGavack, 
New Eng. J. Med., 1945. 232, 95). Rich (Bull. 
Johns Hopkins Hosp., 1944, 74, 1) has shown 
that adrenal damage also plays a role in death 
from severe infections with streptococcus, pneu- 
mococcus. diphtheria bacillus, etc. (see also Sara- 
son, Arch. Int. Med., 1943, 71, 702); the clinical 
use of adrenal extracts in the management of 
serious toxic infections (London and Holman, 
South. M. J., 1945, 38, 596; Perla and Marmors- 
ton. Endocrinology, 1940, 27, 367; Farah. Lancet, 
1938, 1, 777) seems therefore to be justified. 

In alcoholism, Tintera and Lovell (Geriatrics, 
1949, 4, 274) employed the extract according to 
the regimen used for the crisis of Addison's dis- 
ease on the basis of findings indicating that adre- 
nal insufficiency exists in such patients; recovery 
from a period of severe alcoholism was speeded 
and the discomfort was minimized. Voegtlin 
(Quart. J. Stud. Alcohol, 1953, 14, 28) confirmed 
initial benefit with cortisone and corticotropin but 
found no benefit with continued use in preventing 
recurrence of alcoholic excesses. Adrenal cortex 
injection has been recommended for a variety of 
disorders for which no effective therapy is avail- 
able. B 

Toxicology. — Toxic effects from extracts of 
adrenal cortex are almost unknown (Gordon, 
J.A.M.A., 1940, 114, 2549), although desoxycor- 
ticosterone has caused serious untoward effects. 
If the intake of sodium chloride is high, edema 
may develop with adrenal cortex extract. Rapid 
intravenous injection of 5 ml. or more causes the 
effects of epinephrine transiently even though only 
traces of epinephrine remain in most extracts. 

Route of Administration. — Aqueous ex- 
tracts of adrenal cortex, which are usually pre- 
pared from beef adrenal glands, are readily ab- 
sorbed on subcutaneous or intramuscular injec- 
tion; their cortical steroid action persists for 1 to 



4 hours. Although the adrenal steroid hormones 
are absorbed after oral administration (Rogoff, 
J. A.M. A., 1932, 99, 1309; Grollman and Firor, 
/. Biol. Chem., 1935, 109, 189), this route of 
administration has seldom proved to be practical 
(Thorn et al., Endocrinology, 1938, 23, 403, and 
see also under Desoxycorticosterone Acetate). 
There is no apparent therapeutic value in the 
dried suprarenal gland which was long used in 
medicine. 

The usual dose of adrenal cortex injection is 
10 ml., intramuscularly or intravenously, with a 
range of 10 to 100 ml. The dose is repeated as 
often as necessary (see above for details). The 
maximum safe dose is limited by the trace of 
epinephrine (up to 0.2 mg. per 100 ml.) remain- 
ing in the injection. 

Storage. — Preserve "in single-dose or in mul- 
tiple-dose containers, preferably of Type I glass. 
It may be packaged in 50-ml. multiple-dose con- 
tainers." U.S.P. 

Usual Sizes. — 10 and 50 ml. 

AGAR. U.S.P 

Agar-Agar, [Agar] 

"Agar is the dried hydrophilic, colloidal sub- 
stance extracted from Gelidium cartilagineum 
(Linne) Gaillon (Fam. Gelidiacece), Gracilaria 
confervoides (Linnej Greville (Fam. Sphcero- 
coccacem), and from related red algae (Class 
Rhodophycece) ." U.S.P. 

Vegetable Gelatin; Japanese or Chinese Gelatin; Japanese 
Isinglass. Gelosa. Fr. Gelose; Colle du Japon. Ger. Agar 
agar; Vegetabilischer Fischleim; Japanischer Fischleim. 
Sp. Agar-Agar; Agar; Gelosa. 

Quite a number of the algae belonging to the 
Rhodophycece, growing on the coast of southern 
and eastern Asia, California, and the Eastern 
United States, contain large quantities of mucilage 
which is extracted and sold under the name of 
agar-agar. The most important species are Geli- 
dium cartilagineum (L.) Gaillon. Gelidium 
Amansii Lamouroux, Ahnjeltia plicata (Huds.) 
Fries, Endocladia muricata (P. & B.) J. G. Ag., 
Gracilaria confervoides (L.) Greville, and Hypnea 
musciformis (Wulfen) Lamouroux. The algae are 
usually collected during the summer and fall, 
bleached or unbleached, and dried, but the process 
of the manufacture of agar-agar does not take 
place until cold weather, and usually extends from 
November to February. 

According to Tseng (Sci. Monthly, 1944, 59, 
37), Gelidium cartilagineum, a reddish-purple, 
fern-like agarophyte, occurs from Point Concep- 
cion southward along the southern California 
coast, growing on rocks from the low tide mark 
to a depth of 30 or more feet. It is chiefly har- 
vested with a diving rig, the diver pulling the alga 
off by hand. It is dried in the sun and baled, but 
not bleached. 

In processing agar in California, the seaweed 
is soaked in cleaning vats to remove sand, etc., 
placed in pressure cookers where the amorphous 
gelatinous substance is dissolved from the plants 
by hot water, then the resultant hot solution 
passed through filter presses to tubs where it 
forms a gel on cooling. The gel is crushed and 



Part I 



Agar 



31 



poured into cans in the freezing room ; the frozen 
gel is thawed, and the cold water containing im- 
purities is separated from the agar particles in 
rotary vacuum filters. The agar flakes resulting 
are then carried to huge cylindrical stack driers 
where they are dried by ascending currents of hot 
air. Along the coast of Japan the species yielding 
agar are cultivated, poles being anchored in the sea 
to provide supports upon which they multiply. 
The poles are withdrawn and the algae stripped off, 
taken ashore, and dried, then beaten to remove 
sand and shells, and bleached by alternate wash- 
ing and exposure to sunlight preparatory to ex- 
tracting the gelose. 

Wood (/. Council Sci. Ind. Res., 1942, 15, 
295) reported that Gracilaria confervoides is the 
most abundant source of agar in Australia. There 
the algae are gathered from sandy flats, sometimes 
bleached on grass, washed with beaters to remove 
sand, minced, cooked with live steam for 2 to 4 
hours at 95° to 98°, using 4 per cent of the algae 
in the digestion liquid, and adjusting the reaction 
to pH 5 to 6. Solids are removed from the hot 
liquid by centrifuging or by filtration through 
steam heated bag filters; the clarified liquid is 
run into a steam pan, treated with activated char- 
coal and filtered through a plate and frame 
press. The colorless liquid is concentrated at a 
low temperature and allowed to set at 21°, effect- 
ing separation of certain organic impurities. The 
resultant gel is thawed at 35°, washed in running 
water and dried at 40° to 50° in a tunnel drier. 

Most of the agar used in the United States be- 
fore World War II was imported from Japan, al- 
though considerable is produced from red algae 
growing along the coast of lower California. In 

1952, the U. S. imported 337,240 pounds of agar, 
most of which came from Japan and the Korean 
Republic. During the last war production of 
Pacific agar in California was greatly increased 
and, in addition, large amounts of so-called 
"Atlantic coast agar" were manufactured from 
Gracilaria confervoides (L). Greville and allied 
species of red algae gathered off the coast. By 

1953, production of Atlantic coast agar had 
greatly increased and it now represents consider- 
able of the American drug. 

The following varieties of agar are known: 

1. — Ceylon Agar-agar, consisting chiefly of 
Gracilaria lichenoides, Greville, the alga used by 
the Hirundo esculenta in the formation of its 
edible nest. 

2. — Macassar Agar-agar, coming from the 
straits between Borneo and Celebes, consisting 
of impure Eucheuma spinosum, Ag., incrusted 
with salt. 

3. — American Agar-agar, derived from red algae 
growing in the Pacific Ocean off the coast of Cali- 
fornia, including Gelidiutn cartilagineum, G. 
Amansii and Ahnfeltia plicata, which yield the 
product known as "Pacific Coast Agar" and from 
red algae growing in the Atlantic Ocean off the 
coast of southern U. S. and Massachusetts, in- 
cluding Gracilaria confervoides and Hypnea mus- 
ciformis, which yield the "Atlantic Coast Agar." 

4. — Japanese Agar-agar, known as Japanese 
isinglass, derived from a number of algae, espe- 
cially Sphoerococcus compressus, Ag., Gloiopeltis 



tenax, J. Ag., G. cartilagineum (L.) Gaill. and 
other species of Gelidium. Japanese agar differs 
chiefly from American agar by containing the 
large discoid diatom, Arachnoidiscus Ehrenbergii 
Baill. Both varieties contain other species of 
diatoms and sponge spicules. 

5. — Australian Agar-agar, yielded by Gracilaria 
confervoides. 

Constituents. — Agar is composed mainly of 
the calcium salt of a complex carbohydrate sub- 
stance commonly called gelose. Percival and 
Somerville (/. Chem. S., 1937, 1615) were the 
first to establish the structural characteristics of 
the carbohydrate component; they showed the 
major part of it to consist of D-galactose residues 
united by 1,3-glycosidic linkages chiefly of the 
P-type. The presence of L-galactose as well as of 
an esterified sulfuric acid group was also estab- 
lished. Jones and Peat (/. Chem. S., 1942, 225) 
consider the chief constituent of agar to be the 
sulfuric acid ester of a linear polygalactose in 
which the repeating unit is composed of nine 
D-galactopyranose residues terminated at the re- 
ducing end by one residue of L-galactose. The 
D-galactose units are mutually combined by 1,3- 
glycosidic linkages, but the L-galactose residue is 
attached to the chain through position 4; this 
residue is esterified at the sixth carbon atom with 
sulfuric acid. Percival and Thomson (/. Chem. S., 
1943, 750) reported analytical data on the hy- 
drolysis of certain agar derivatives which are at 
variance with those of Jones and Peat and are 
of the opinion that the structure proposed by the 
latter investigators is oversimplified. 

Itano (Proc. Imp. Acad. Tokyo, 1933, 9, 398) 
found that commercial agar may contain from 
24.5 to 101.9 parts per million of iodine. This 
may be reduced to 6 or 7 p.p.m. by suitable 
purification. 

When a solution of agar is cooled, even that 
of 1 in 500 parts of water a colorless, trans- 
parent, and stiff jelly is obtained, which, when 
heated with moderately strong nitric acid, yields 
mucic and oxalic acids. It dissolves on heating 
with acidulated water without yielding a jelly on 
cooling. 

Description. — "Unground Agar usually oc- 
curs in bundles consisting of thin, membranous, 
agglutinated pieces or in cut, flaked or granulated 
forms. It may be externally weak yellowish 
orange, yellowish grc.y or pale yellow or colorless. 
It is tough when damp, brittle when dry. It is 
odorless or has a slight odor and a mucilaginous 
taste. 

"Histology. — In water mounts Agar appears 
granular and somewhat filamentous; a few frag- 
ments of the spicules of sponges and a few frus- 
tules of diatoms may be present; in Japanese 
Agar, the frustules of Arachnoidiscus Ehrenbergii 
Baillon occur, which are disc-shaped and from 
100 to 300 \i in diameter. 

"Powdered Agar is white to yellowish white or 
pale yellow; in chloral hydrate T.S. its fragments 
are transparent, more or less granular, striated, 
angular, and occasionally containing frustules of 
diatoms. 

"Solubility. — Agar is insoluble in cold water, 
but soluble in boiling water." U.S.P. 



32 Agar 



Part I 



Standards and Tests. — Identification. — (1) 
Some fragments of agar are colored bluish black, 
and some areas reddish to violet, by iodine T.S. 
(2) On boiling agar with 65 times its weight of 
water for 10 minutes, with constant stirring, then 
adjusting to 1.5 per cent concentration of agar by 
addition of hot water, a clear liquid results; at 
32" to 39° it congeals to form a firm, resilient gel, 
the melting point of which is not below 85°. 
Water. — Not over 20 per cent when determined 
by drying at 105° for 5 hours. Acid-insoluble ask. 
— Not over 0.5 per cent, on a dry weight basis. 
Total ash. — Not over 6.5 per cent, on a dry weight 
basis. Foreign organic matter. — Not over 1 per 
cent. Foreign insoluble matter. — When calculated 
on a dry weight basis not over 1 per cent of resi- 
due is obtained by filtering a solution of 1.5 Gm. 
of agar in 200 ml. of hot aqueous solution through 
a Gooch crucible and drying the latter at 105°. 
Foreign starch. — No blue color is produced on 
adding iodine T.S, to a solution prepared by boil- 
ing 100 mg. of agar with 100 ml. of water, then 
cooling. Gelatin. — No turbidity develops in 10 
minutes following addition of 5 ml. of picric acid 
T.S. to an equal volume of a solution made by 
dissolving 1 Gm. of agar in 100 ml. of boiling 
water and cooling to about 50°. Water absorption. 
— 5 Gm. of agar is placed in a 100-ml. graduated 
cylinder and enough water added to the 100 ml. 
mark; after 24 hours of maceration at 25° not 
more than 75 ml. of water should be obtained by 
pouring off the liquid, through glass wool, into 
another graduated cylinder, corresponding to the 
absorption by agar of at least five times its weight 
of water. U.S.P. 

Tseng (Science, 1945, 101, 597) observed that 
it is not yet definitely known whether the so- 
called agar from sources (agarophytes) other than 
species of Gelidium is identical with the latter. 
He suggested that a definition or specification for 
agar should include the requirement that a one 
per cent neutral, aqueous solution of it should 
set at 35° to 50° to a firm gel, and the latter 
melt at 80° to 100°. Tseng also proposed the new 
term phycocolloid to designate the polysaccharides 
which are derived from the brown and the red 
seaweeds and which are able to form colloidal 
systems when dispersed in water. 

The presence of Japanese agar may often be 
detected by the characteristic diatoms; a proce- 
dure based on this was described by Schneider 
(Pac. Pharm., 1912, p. 35). Identification meth- 
ods utilizing characteristic color and precipitation 
reactions are described by Cannon (J.A.O.A.C., 
1939, 22, 92, 726) and by Pirie (Brit. J. Exp. 
Path., 1936. 17, 269). 

Uses. — The therapeutic value of agar is de- 
pendent on its ability to absorb and retain water 
as it passes through the gastrointestinal tract, 
giving bulk to the intestinal contents and also 
serving as a lubricant. Its mechanical action is. 
therefore, analogous to that of the cellulose of 
vegetable foods. Because it aids in maintaining 
regularity of bowel movements, agar has been 
widely used in the treatment of chronic constipa- 
tion. It is frequently combined with cascara or 
some other vegetable cathartic because it is com- 
monly believed that agar does not stimulate peri- 



stalsis in atonic intestinal muscle, although Chase, 
cited by Tseng (Sci. Monthly, 1944, 58, 24), 
stated that it does contain laxative principles 
which excite peristaltic activity. Eisner et al. 
(Ztschr. physiol. Chem., 1937, 246, 244) re- 
ported that agar is an anticoagulant. 

Agar is best administered in the form of a gel, 
prepared by dissolving it in hot water and cool- 
ing, flavored and sweetened as desired; at body 
temperature agar absorbs little water and does 
not provide much more bulk than when dry 
(Gray and Tainter, Am. J. Digest. Dis., 1941, 
8, 130). It is, however, also commonly cut into 
small pieces and eaten like cereal; chocolate- 
coated preparations of agar have been marketed. 
In many proprietary preparations it is combined 
with mineral oil as an emulsion; in such prepara- 
tions the agar serves primarily as an emulsifying 
agent and, although the character of the stool is 
modified, little is added to the bulk (Nelson, 
Internat. Med. Digest, 1943, 42, 308) because 
of the relatively small amount of agar present. 

Agar is much used in the preparation of suspen- 
sions, emulsions, jellies, hydrophilic suppositories, 
etc. For years it has served as the basis of many 
culture media employed by bacteriologists. War- 
time dearth of supply stimulated development of 
methods for recovering agar from used culture 
media (Blundell, Science, 1943, 97, 76; Brodie 
and Stiven, /. Hygiene, 1942, 46, 498). Agar is 
used as food in the Orient; while it contains 60 
per cent of carbohydrates the latter consist largely 
of indigestible hemicelluloses which may actually 
decrease absorption of the nutrient substances 
that are present. Agar is also extensively used in 
bakery products, in clarifying liquids, in making 
"health foods," in confections, and in ice cream. 
In dentistry it serves as an impression mold. For 
further information concerning uses of agar see 
Tseng (Sci. Monthly, 1944, 58, 24; 1944, 59, 

37). m 

Dose. — The usual dose is 4 Gm. (approxi- 
mately 60 grains) once or twice daily; the range 
of dose is 4 to 16 Gm. 

Off. Prep. — Phenolphthalein in Liquid Petro- 
latum Emulsion, N.F. 



NORMAL HUMAN SERUM 
ALBUMIN. U.S.P. 

Normal Serum Albumin (Human), [Albuminum Seri 
Humanum Normale] 

"Normal Human Serum Albumin is a sterile 
preparation of serum albumin obtained by frac- 
tionating blood from healthy, human donors. It is 
either a solution containing, in each 100 ml., 25 
Gm. of the serum albumin osmotically equivalent 
to 500 ml. of normal human plasma, or a dried 
preparation suitable for restoration to an appro- 
priate volume for clinical use. It contains no 
added bacteriostatic agent, but each 100 ml. of 
the liquid form may contain as a stabilizing 
agent either 0.04 mol of sodium acetyltryptopha- 
nate or 0.02 mol each of sodium acetyltryptopha- 
nate and sodium caprylate. If prepared from 
plasma containing a mercurial preservative, it 
contains not more than 20 meg. of mercury per 
Gm. of albumin. Not less than 97 per cent of the 



Part I 



Albumin, Normal Human Serum 33 



total protein of Normal Human Serum Albumin 
is albumin." U.S.P. 

Normal human serum albumin is obtained by 
fractionation of human plasma and constitutes up 
to 90 per cent of fraction V (for further informa- 
tion see Normal Human Plasma). 

Description. — "Liquid Normal Human Serum 
Albumin is a moderately viscous, clear, brownish 
fluid. It is substantially odorless. Dried Normal 
Human Serum Albumin has a light yellow to deep 
cream color." U.S.P. 

Standards and Tests. — Sodium content. — 
Not more than 0.0132 Gm. of Na per Gm. of 
albumin. Water content of dried serum albumin. 
— Not over 1 per cent, when determined by drying 
to constant weight at room temperature over 
phosphorus pentoxide at a pressure of not more 
than 1 mm. of mercury. Other requirements. 
— Complies with the identity, safety, sterility, 
and stability tests and other requirements of the 
National Institutes of Health of the United States 
Public Health Service, including the release of 
each lot individually before its distribution. U.S.P. 

Uses. — Human serum albumin was developed 
during World War II as a compact, stable, easily 
transportable blood substitute for use in emer- 
gency treatment of shock (see under Normal 
Human Plasma). When its use was later ex- 
tended to include treatment of hypoproteinemic 
states and nephrosis, a salt-poor form was pre- 
pared in which the sodium content is one-seventh 
or less than that of an osmotically equivalent vol- 
ume of plasma. Heating to 60° for 10 hours de- 
stroys the virus of serum hepatitis and also 
bacteria so that mercurial preservatives are no 
longer needed. Use of human albumin intrave- 
nously does not carry the risk of homologous 
serum hepatitis that exists when pooled plasma 
or serum is used and to a lesser extent with 
single blood donations (Paine and Janeway, 
J.A.M.A., 1952, 150, 199). 

Shock. — In emergency treatment of shock 
serum albumin is of unquestioned value. An in- 
crease in plasma volume of 8 to 18 ml. for each 
Gm. of albumin administered is to be expected 
but extra fluid must be given to dehydrated pa- 
tients to achieve maximum benefit (Gibson, New 
Eng. J. Med., 1948, 239, 579). Human serum 
albumin does not restore loss of oxygen-carrying 
capacity resulting from loss of blood due to 
hemorrhage. 

Nephrosis. — Serum albumin has been used ex- 
tensively in the nephrotic syndrome, but with dis- 
appointing results. Seegal and Wertheim (Bull. 
N. Y. Acad. Med., 1949, 25, 605) reported ob- 
servations on 81 patients given 103 courses of 
albumin under well-controlled conditions. Daily 
doses varied from 7.5 to 100 Gm. Transient and 
incomplete diuresis was seen in 47 per cent of 
treatments; questionable effect was noted in 10 
per cent; no diuresis was found in the remaining 
43 per cent. Most of the injected albumin ap- 
peared in the urine in 24 hours. Such therapy did 
not affect the natural course of the underlying 
disease. Janeway (J.A.M.A., 1948, 138, 864) 
concluded that the place of albumin in the ther- 
apy of nephrosis is limited, that its use is enor- 
mously wasteful and expensive, and that it does 



not alter the course of the disease. However, in 
certain cases in which other methods of therapy 
fail, and in which edema is incapacitating, he has 
found it useful. 

Cirrhosis of the Liver. — Conflicting reports 
have appeared on the use of albumin in cirrhosis. 
Kunkel et al. (I. Clin. Inv., 1948, 27, 305) treated 
17 patients with doses of 100 to 2000 Gm. of 
albumin. Patients with low serum albumin and 
ascites of short duration responded most readily, 
although 14 of 15 patients with ascites eventually 
lost their fluid after albumin therapy. With 
smaller doses for shorter periods, Thorn et al. 
(ibid., 1946, 25, 304) and Patek et al. (ibid., 
1948, 27, 135) were unable to produce a favor- 
able result. Falcon and coworkers (ibid., 1949, 
28, 583) saw 3 fatal hemorrhages from esophageal 
varices shortly after giving albumin to 20 cirrhotic 
patients. Jacobi et al. (J. Pediatr., 1946, 29, 177) 
found an excellent response in 2 infants with 
erythroblastosis fetalis and edema following ad- 
ministration of 30 and 12.5 Gm. of albumin, 
respectively. Post et al. (Arch. Int. Med., 1951, 
87, 775) used salt-poor human albumin intrave- 
nously in patients critically ill with decompen- 
sated hepatic cirrhosis with general clinical im- 
provement, gain in appetite, strength and body 
tissue, as well as decline of icterus along with the 
diuresis. They concluded that albumin has a place 
in the management of patients with severely de- 
compensated hepatic cirrhosis for whom adequate 
dietary therapy cannot be provided. Ricketts et 
al. (J. Clin. Inv., 1951, 30, 1157) found that 
albumin intravenously did not correct the de- 
creased renal excretion of sodium in these cases; 
the albumin increased in the ascitic fluid and 
tissue edema fluid moved to the abdominal peri- 
toneal space. Abnormal capillary permeability 
during the active disease is probably a factor. 

The final evaluation of the place of albumin in 
therapy must await definitive studies of the me- 
tabolism of injected albumin in normal and ab- 
normal states. This agent has potent osmotic 
activity the extent of which depends upon the 
state of protein nutrition and the permeability of 
capillaries throughout the body and especially in 
the glomerulus. There is no evidence of renal 
damage from increased proteinuria. A positive 
nitrogen balance following administration of albu- 
min may merely mean inert retention in extra- 
cellular fluid rather than actual metabolism. 

Studies with albumin tagged with radioactive 
iodine-131 demonstrated that depletion of labile 
albumin stores can be correlated with presence of 
ascites (Tyor and Gayer, South. M. J., 1952, 45, 
144) ; it is suggested that albumin metabolism 
proceeds at a constant rate and is demonstrably 
altered only in the terminal stages of liver dis- 
ease. Albumin tagged with iodine-131 has also 
been used for the study of peripheral circulation 
(Krieger et al., Ann. Surg., 1952, 136, 357). 

The usual dose, intravenously, is 100 to 200 
ml., representing 25 to 50 Gm. of albumin, re- 
peated as necessary. In terms of body weight the 
dose is 2.2 ml. per Kg., injected at a rate of 2 ml. 
per minute. 

Labeling. — "The container label bears the 
name Normal Serum Albumin (Human); the 



34 Albumin, Normal Human Serum 



Part I 



amount in Gm. of albumin present; in the case of 
liquid serum albumin the total volume of the 
contents and the amount and kind of stabilizing 
agent; the osmotic equivalent in terms of plasma; 
the lot number; the expiration date, which for 
liquid serum albumin is not more than 5 years 
after date of manufacture or date of issue, and 
for dried serum albumin not more than 8 years 
after date of manufacture or date of issue; the 
manufacturer's name; the statement, 'Contains no 
preservative'; and in the case of liquid serum 
albumin the statements, 'Caution: Do not use if 
turbid,' and 'Salt Poor. Additional fluids are re- 
quired when administered to patient with marked 
dehydration,' and in the case of dried serum albu- 
min the statement, 'Use within 3 hours after res- 
toration.' The package label bears, in addition to 
the above, the manufacturer's license number 
and address, and the recommended storage tem- 
perature." U.S.P. 

Storage. — Preserve "at a temperature between 
2° and 10°. Exposure for short periods to a higher 
temperature will cause no significant deterioration. 
Preserve dried Normal Human Serum Albumin 
at room temperature, not exceeding 37°. Dis- 
pense Normal Human Serum Albumin in the 
unopened container in which it was placed by the 
manufacturer." U.S.P. 

Usual Sizes. — 20 and 50 ml., equivalent to 
100 and 250 ml. of plasma. 

ALCOHOL. U.S.P,. B.P. (LP.) 

Ethanol, Ethyl Alcohol, Spiritus Vini Rectificatus, 
[Alcohol] 

CH3.CH2OH 

"Alcohol contains not less than 92.3 per cent by 
weight, corresponding to 94.9 per cent by volume, 
at 15.56°, of C2H5OH." U.S.P. The B.P. requires 
from 94.7 per cent to 95.2 per cent v/v (92.0 to 
92.7 per cent w/w) of C2H6O. The LP. requires 
Ethanol to contain not less than 95.1 per cent 
v/v and not more than 96.8 per cent v/v, corre- 
sponding to not less than 92.5 per cent w. w and 
not more than 95.0 per cent w/w of C2H5OH. 

Ethyl Hydroxide; Rectified Spirit; Spirit of Wine. 
Spiritus Rectificatus; Spiritus. Fr. Alcool ethylique a 95 
degres centesimaux; Alcool officinal. Ger. Weingeist; Al- 
kobol; Athylalkohol ; Branntwein. It. Alcool rettificato; 
Spirito di vino. Sp. Alcohol; Espiritu de vino. 

Alcohol has been made for many centuries by 
the fermentation of carbohydrates by yeast. 
Utilizable carbohydrate-containing materials in- 
clude molasses, sugar cane, fruit juices, corn, 
barley, wheat, potato, wood and waste sulfite liq- 
uors. As yeast is capable of fermenting only 
D-glucose, D-fructose, D-mannose, and D-galactose 
it is essential that more complex carbohydrates 
be converted to one or more of these simple 
sugars before they can be fermented. This is 
variously accomplished; for example, yeasts con- 
tain enzymes which hydrolyze disaccharides to 
monosaccharides, starches may be saccharified by 
hydrolysis with acids or by the enzyme diastase 
from malt, cellulose is converted to sugars by 
hydrolysis with acid under pressure. 

The net reaction that occurs when a hexose, 
glucose for example, is fermented to alcohol may 



be represented as follows: CeHi20ff-»2C2H50H-f 
2CO2. The mechanism of the process is, however, 
exceedingly complex and many investigators have 
studied it in detail. Of the several theories which 
have been proposed, that of Meyerhof is sup- 
ported by considerable experimental evidence. 
According to this theory, both glucose and fruc- 
tose are by several steps converted to the common 
intermediate substance fructose- 1,6-diphosphoric 
acid, the phosphoric acid being supplied through 
the "adenylic acid system" of yeast. The fruc- 
tose-l,6-diphosphoric acid is enzymatically split 
into an equilibrium mixture of the three-carbon 
molecules 3-glyceraldehyde phosphate and dihy- 
droxyacetone phosphate, which are isomeric and 
convertible one into the other. In the main 
sequence of fermentation reactions the former 
substance is successively converted to 3-phospho- 
gly eerie acid, 2-phosphoglyceric acid, phospho- 
pyruvic acid and pyruvic acid, which last under- 
goes decarboxylation to acetaldehyde and then, in 
a reaction involving a molecule of 3-glyceralde- 
hyde phosphate, is enzymatically reduced to ethyl 
alcohol. A minor sequence of reactions, leading 
to the production of a small amount of glycerin, 
starts with dihydroxyacetone phosphate which is 
first reduced to alpha-glycerol phosphate and then 
dephosphorylated to glycerin. Fusel oil and suc- 
cinic acid are also obtained in very small amounts. 
Formation of both constituents appears to be 
associated with nitrogen metabolism of the yeast 
cell and is minimized if a readily available source 
of nitrogen is present in the fermentation mixture. 
The chief constituents of fusel oil are isoamyl 
alcohol and D-amyl (active amyl) alcohol. 

In the years immediately before World War II 
approximately 90 per cent of the alcohol pro- 
duced in the United States utilized black-strap 
molasses as the starting material. Manufacture 
of alcohol from molasses is much simpler than 
from grain in that the milling, cooking and malt- 
ing (by which saccharification of starch is accom- 
plished) are omitted; molasses does not require 
an initial hydrolysis as it contains fermentable 
sugars. The process consists of the following 
steps: (1) weighing of the molasses, (2) mixing 
with water, (3; sterilizing, to prevent contami- 
nation with organisms which may influence the 
course of the fermentation, (4) cooling or dilut- 
ing with cold water, (5) charging the fermenters 
with the dilute molasses, (6) addition of pure 
yeast culture (generally Saccharomyces cerevisia), 
sulfuric acid (to invert the sucrose in the mo- 
lasses), and yeast food (ammonium sulfate), (7) 
fermentation for 36 to 48 hours, (8) distillation 
of the "beer," which contains 6.5 to 8.5 per cent 
by volume of alcohol, to yield a distillate contain- 
ing 95 per cent by volume of alcohol. 

Ethyl alcohol from cellulose was first produced 
commercially in this country during 1910, in a 
plant constructed for this purpose in South Caro- 
line. Approximately 20 gallons of alcohol was 
produced from each ton of sawdust; the latter 
was hydrolyzed by sulfuric acid under pressure. 
A process developed by the German Bergius in- 
creases the yield to 75 to 80 gallons per ton of 
wood. A plant under construction at Springfield, 
Oregon, had been planned to have a capacity of 



Part I 



Alcohol 



35 



about 11,500 gallons of alcohol daily from some 
230 tons of wood waste; construction of it was 
stopped at the close of World War II. 

At present, approximately half of the total in- 
dustrial alcohol production is by synthesis in- 
volving hydration of ethylene. Abundant supplies 
of ethylene are obtained from natural and coke 
oven gases, from waste gases of the petroleum 
industry, and from pyrolysis of ethane, propane, 
and butane. The older and by far the more widely 
used synthesis involves indirect hydration of 
ethylene; in this process ethylene is reacted with 
concentrated sulfuric acid to form ethyl hydrogen 
sulfate and dimethyl sulfate, both of which react 
with water to yield ethyl alcohol and sulfuric 
acid. This indirect process was developed because 
the process of direct hydration originally em- 
ployed was slow. Recently, however, direct hydra- 
tion has become feasible through use of high 
pressures, low temperatures, suitable catalysts 
(such as aluminum oxide), and by recycling of 
reactant gases. It is expected that production of 
alcohol from ethylene will increase, not only be- 
cause of the growing availability of ethylene but 
also because, when molasses prices are high, alco- 
hol can be produced more cheaply from ethylene 
than from any other raw material. 

In another synthesis acetylene is catalytically 
hydrated to acetaldehyde, which is then hydro- 
genated, in the presence of a catalyst, to ethyl 
alcohol; this process was used during World 
War I. 

The term proof spirit, as used in the United 
States, refers to a product containing 50 per cent 
by volume of C2H5OH; it is sometimes desig- 
nated as 100 proof alcohol. The strength of any 
other solution of ethyl alcohol may be expressed 
in "proof" by multiplying the concentration of 
C2H5OH, by volume, by two. Thus an alcohol 
containing 60 per cent by volume of C2H5OH 
is 120 proof, and official alcohol of 95 per cent 
by volume concentration of C2H5OH is 190 
proof. English proof spirit contains 49.3 per cent 
C2H5OH by weight, or 57 per cent by volume; 
it is materially stronger than United States proof 
spirit. 

Alcohol represents a constant-boiling mixture 
of ethanol (95.57 per cent by weight) and water 
(4.43 per cent by weight) ; the boiling point is 
78.2°, while anhydrous alcohol boils at 78.3°. It is 
not possible to obtain anhydrous alcohol by direct 
distillation (see Dehydrated Alcohol). 

Alcohol has many and varied industrial uses. 
It is important as a general solvent, and is in- 
dispensable for dissolving perfumes, flavoring ex- 
tracts, and in the preparation of pharmaceuticals. 
In addition it is essential in the synthesis of many 
organic substances, including ether and chloro- 
form. It serves as a fuel, either liquid or in the 
form of "solidified alcohol," and has been used 
alone or mixed with gasoline as a motor fuel. 
"Solidified alcohol" contains 5 per cent methanol. 

Denatured Alcohol. — The U. S. government 
has established regulations authorizing the addi- 
tion of substances to alcohol which render it unfit 
for beverage purposes although it is suitable for 
industrial use. The liquid so treated is termed 
denatured alcohol. 



The U. S. Internal Revenue Department has 
authorized the use of a number of substances for 
denaturing alcohol, but such alcohol must be pre- 
pared under the supervision of an official of the 
Department, at specified depots. Some of these 
formulas provide an alcohol for burning purposes 
or for use as a special solvent, other represent 
the reactant mixture for preliminary manufactur- 
ing processes, such as a mixture of sulfuric acid 
and alcohol for the subsequent production of 
ether, while still other formulas, identical with 
official formulas such as iodine tincture, soap lini- 
ment, etc., have been authorized and thus make 
it possible to have these products manufactured 
from tax-free alcohol at greatly reduced cost. (See 
also Alcohol Rubbing Compound.) These prep- 
arations may therefore be purchased from large 
dealers at prices which are less than the cost of 
the raw material if bought through the usual 
channels of trade. 

Under the title Industrial Methylated Spirit 
(Spiritus Methylatus Industrialis) the B.P. recog- 
nizes a mixture, made by a legally authorized 
methylator, of 19 volumes of 95 per cent alcohol 
with 1 volume of approved wood naphtha. It is 
of the quality known as "66 O.P. industrial meth- 
ylated spirits." Use of this product is permitted 
by the B.P. in the preparation of certain liniments 
and test solutions and in the manufacture of cer- 
tain extracts and resins in which none of the 
solvent remains in the finished product. 

Description. — "Alcohol is a transparent, color- 
less, mobile, volatile liquid. It has a slight, char- 
acteristic odor and a burning taste. Alcohol is 
readily volatilized even at low temperatures and 
boils at about 78°. It is flammable. Alcohol is 
miscible with water, with ether, and with chloro- 
form. When Alcohol is diluted with an equal 
volume of water the mixture is clear and remains 
clear for 30 minutes after cooling to 10°. The 
specific gravity of Alcohol is not more than 0.816 
at 15.56°, indicating not less than 92.3 per cent 
by weight, or 94.9 per cent by volume, of 
C2H5OH." U.S.P. The temperature 15.56° C. is 
equivalent to 60° F., the standard temperature 
employed in stating concentrations of alcohol in 
per cent by volume. 

Standards and Tests. — Acidity. — Not more 
than 0.9 ml. of 0.02 N sodium hydroxide is re- 
quired to neutralize 50 ml. of alcohol, using 
phenolphthalein T.S. as indicator. Non-volatile 
residue. — Not over 1 mg. from 40 ml. of alcohol, 
the residue being dried at 105° for 1 hour. Fusel 
oil constituents. — No foreign odor is perceptible 
when the alcohol is spontaneously evaporated 
from a mixture of 10 ml. of alcohol, 5 ml. of 
water and 1 ml. of glycerin placed on odorless 
absorbent paper. Amyl alcohol or non-volatile, 
carbonizable substatices, etc. — No red or brown 
color is produced on adding a few drops of sulfuric 
acid to the nearly dry residue from the evapora- 
tion of 25 ml. of alcohol in a porcelain dish, pro- 
tected from dust. Aldehydes and other foreign 
organic substances. — The pink color produced by 
the addition of 0.1 ml. of 0.1 TV potassium per- 
manganate to 20 ml. of alcohol in a thoroughly 
cleansed glass-stoppered cylinder, the solution 
being maintained at 15°, does not entirely disap- 



36 



Alcohol 



Part I 



pear in 5 minutes. Ketones, isopropyl alcohol, 
and tertiary butyl alcohol. — No precipitate forms 
within 3 minutes when a mixture of 1 ml. of 
alcohol, 3 ml. of water and 10 ml. of mercuric 
sulfate T.S. is heated on a bath of boiling water. 
Methanol. — No violet color appears on heating 
for 10 minutes at 60° a mixture of 5 ml. of freshly 
prepared chromotropic acid T.S. and a solution 
obtained when 1 drop each of alcohol, water, 
dilute phosphoric acid (1 in 20), and potassium 
permanganate solution (1 in 20) are mixed, al- 
lowed to stand 1 minute, treated with 1 in 20 
sodium bisulfite solution to discharge the per- 
manganate color and, if a brown color remains, 1 
drop of the diluted phosphoric acid added to pro- 
duce a colorless solution. U.S.P. 

The B.P. specific gravity range is 0.815 to 0.817 
at 15.5/15.5° and the refractive index, measured 
at 20°, may vary from 1.3637 to 1.3639. 

Incompatibilities. — The addition of alcohol 
to aqueous solutions may cause the precipitation 
of alcohol-insoluble compounds, such as numerous 
inorganic and organic salts, and gums such as 
acacia. Oxidizing agents may convert alcohol into 
acetaldehyde and acetic acid. 

Uses. — Alcohol has a variety of external and 
internal uses in medicine and is important in 
pharmacy. The local action of alcohol is mildly 
irritant, feebly anesthetic and distinctly germi- 
cidal and astringent. Some have contended that 
the most effective concentration for local anti- 
sepsis is from 60 to 70 per cent by weight in 
water; careful studies by Hatfield et al. (Surgery, 
1943, 13, 931), in which numerous antiseptics 
were compared by a modification of the Price 
technic (v.i.), showed that 95 per cent ethyl 
alcohol by volume is superior in its ability to kill 
bacteria on the skin (see also Morton, Ann. N. Y. 
Acad. Sc, 1950, 53, 191). Such concentrations 
of alcohol will destroy most pathogenic bacteria 
within a relatively short time, but more resistant 
spore-bearing organisms survive even prolonged 
exposure. Alcohol is used for general anesthesia, 
local destruction of nerves in lieu of surgical 
excision, as an appetizer and even for parenteral 
or oral nutrition. Its misuse creates vast social 
and economic and police problems and treatment 
of intoxication is a frequent chore. 

Psychomotor Action. — Alcohol belongs, phys- 
iologically as well as chemically, to the group of 
aliphatic narcotics. In large doses it produces 
coma analogous to ether anesthesia. Extensive 
studies have permitted correlation of the con- 
centration of alcohol in blood, and also in urine 
and expired air, with action on the central nervous 
system. This information is more of medicolegal 
than therapeutic importance and the figures must 
be interpreted in the light of knowledge of absorp- 
tion and excretion in relation to time. Alcohol is 
absorbed rapidly from the gastrointestinal tract; 
in the ordinary doses of alcoholic beverages about 
20 per cent is absorbed by the stomach and the 
remainder in the intestine. The rate of absorption 
is altered by the presence or absence of food, as 
well as the type of food present; protein as well 
as fat delay absorption. Alcohol is easily and 
rapidly diffusible and at equilibrium attains a 
concentration in tissues related to the concentra- 



tion of water present in the extracellular and 
intracellular compartments. From 90 to 98 per 
cent of ingested alcohol is metabolized in the body 
(v.i.) and only 2 to 10 per cent is excreted as 
such, chiefly in the urine and to a lesser extent in 
expired air. Only traces are found in sweat, milk 
and bile. According to Ladd and Gibson (Ann. 
hit. Med., 1943, 18, 564), the concentration in 
urine is about 1.35 times that in arterial blood; 
it must be remembered that a large collection of 
urine in the bladder represents the arterial blood 
concentration over the period of time this urine 
was secreted by the kidneys and not the blood 
concentration at the time the urine is voided. In 
expired air the concentration is approximately 
1/2000 of that in arterial blood. In the obviously 
intoxicated person, the urine may contain as much 
as 5 Gm. per liter and the expired air a few mg. 
per liter. With ingestion of cocktails containing 
1 ounce of whisky (45 per cent alcohol by vol- 
ume) the following blood concentrations may be 
observed, on the average: 20 minutes after the 
first cocktail, 20 mg. per 100 ml.; at 45 minutes, 
having consumed a second cocktail at 20 minutes, 
40 mg. per 100 ml.; at 60 minutes, having con- 
sumed a third cocktail at 40 minutes, 60 mg. per 
100 ml.; subsequently one ounce of whisky per 
hour will maintain a blood concentration of ap- 
proximately 60 mg. per 100 ml. Without further 
intake the concentration decreases at the rate of 
about 10 mg. per 100 ml. per hour. As an ap- 
proximation, 12 ounces of beer or 3 ounces of 
wine represent the alcohol content of 1 ounce of 
whiskey. 

The initial "stimulating" effect of alcohol, which 
is actually a depression of the inhibitory activi- 
ties of the cerebral cortex, is associated with a 
blood concentration of about 30 mg. per 100 ml. 
(Miles, /. Pharmacol., 1922, 20, 265). At this 
stage performance may be improved insofar as 
elimination of embarrassment is helpful but tests 
show that there is some loss in fine discrimination. 
At 50 mg. per 100 ml., the individual is not 
"drunk" but is in the flippant stage of unbounded 
self-confidence and pleasure with himself and the 
world in general. He may neglect some social 
niceties and knock over an occasional article. At 
100 mg. per 100 ml., the individual is "giddy," 
and at 150 mg. becomes clumsy. There is then 
definite difficulty in adjusting to the environment 
and the individual may be amused, ashamed or 
angry with his incapacity. Between 150 and 300 
mg. per 100 ml. there is progressive deterioration 
of the function of the central nervous system; at 
200 mg. the person is incoordinated and uncon- 
trollable and at 300 mg. sleepy and maudlin; in 
common parlance, he is "drunk." There is usually 
emotional disturbance from bitter tears to raucous 
laughter, progressive incoordination resulting in 
inability to dress or undress, and drowsiness with 
intermittent sleep. With concentrations over 300 
mg., the condition resembles that of the second 
stage of anesthesia (see under Ether) ; respiration 
is deep and irregular, vomiting is frequent, even 
when the alcohol has been injected intravenously 
and there is no gastric irritation, persuasion is 
futile and coercion causes violent struggling. At 
a concentration of 400 mg., anesthesia is pro- 



Part I 



Alcohol 



37 



found; at 500 mg., the respiratory center is de- 
pressed and death is likely if the concentration 
remains above 500 mg. for 12 hours. Up to the 
anesthetic concentration, however, there is little 
effect on the respiratory or vasomotor centers in 
the medulla oblongata. Newman (Science, 1949, 
109, 594) estimated that the maximum consump- 
tion in 24 hours short of producing coma in a 
70-kilogram man was 26^ ounces of 100 proof 
whisky. 

Circulation. — The question of the effects of 
alcohol on the circulation has been the subject 
of much study and dispute. When administered 
in moderate quantity, it usually does not produce 
any marked change in the blood pressure. On the 
other hand, the rapidity of the flow of blood 
through the vessels is distinctly accelerated. This 
combination of effects can be most readily ex- 
plained by simultaneous increase in the cardiac 
action and dilatation of the blood vessels. In- 
creased muscular activity accounts for some in- 
crease in circulation. Grollman (Quart. J. Stud. 
Alcohol, 1942, 3, 5) believes the vasodilatation 
is due to the depressant effect of alcohol on the 
vasomotor centers in the brain. Further, he attrib- 
uted much of what effect alcohol does have on 
the circulation to reflex activity from the mouth 
and to psychic components. 

The widening of the blood vessels is most 
noticeable in the vessels of the skin. Horwitz et al. 
(Am. J. Med. Sc, 1949, 218, 669) compared 
the efficacy of various vasodilators and found that 
a dose of 60 to 100 ml. of whisky was most effec- 
tive in increasing blood flow to the fingers and 
to a lesser extent to the toes. Except for the 
habituating action of alcohol it is an effective 
symptomatic remedy in Buerger's disease. It may 
also be useful in cases of embolism of the smaller 
peripheral arteries. With blood concentrations 
which permit ambulation there is little effect on 
the heart. McDowall (/. Pharmacol., 1925, 25, 
289) found that large doses of alcohol cause a 
marked fall in the venous pressure and believes 
that many of the clinical benefits which have fol- 
lowed the use of alcohol can be attributed to a 
dilatation of the veins. Grollman points to its 
capacity to allay worry and anxiety as the most 
valuable effect of alcohol on the circulation, the 
sedative action being paramount. 

In angina pectoris alcoholic beverages have a 
long-established reputation. Stearns et al. (New 
Eng. J. Med., 1946, 234, 578) found that alcohol 
decreased the duration of the symptoms but not 
of the objective findings as a result of the 2 -step 
exercise test in cases of coronary insufficiency. 
In an attack of angina pectoris, nitroglycerin is 
certainly preferred, since the action of alcohol is 
that of a sedative rather than a coronary dilator 
(Russek et al., J.A.M.A., 1953, 153, 207). Pro- 
phylactic use of wine at the end of the day's work 
seems rational. Studies of cerebral blood flow by 
Battey et al. (ibid., 1953, 152, 6) found that 
alcohol is not an effective cerebral vasodilator; 
in humans, at a blood alcohol concentration of 
68 mg. per 100 ml, there was no effect on cerebral 
blood flow or oxygen consumption, but at 320 mg. 
per 100 ml. the cerebral flow was increased while 
the oxygen consumption was decreased. 



Metabolism. — When a moderate quantity of 
alcohol is ingested, from 90 to 95 per cent is com- 
pletely oxidized in the system, only traces of the 
drug being recoverable from either the urine or 
breath. The oxidation of this hydrocarbon yields 
energy amounting to 7 Calories per gram, the 
oxidation products being carbon dioxide and water. 
The experiments of Atwater and Benedict (Mem- 
oirs of the National Academy of Science, 1902, 
7), of Mitchell (/. Nutrition, 1935, 10, 311) and 
of many others, seem to prove that small amounts 
of alcohol are entirely capable of replacing, to a 
considerable degree, a portion of the carbohydrate 
foodstuffs. 

The metabolism of alcohol is initiated in the 
liver by conversion to acetaldehyde and thence 
to acetic acid which may be metabolized in many 
tissues in the manner of degradation products of 
carbohydrate. The respiratory quotient of alcohol 
is 0.667, and its combustion may spare that of 
carbohydrate, fat and protein. Alcohol cannot be 
stored in the body and in the absence of food it 
will not form liver glycogen. Goldfarb et al. 
(J. Clin. Inv., 1939, 18, 581) found that simul- 
taneous administration of dextrose and insulin 
increased the rate of oxidation of alcohol; this 
may prove helpful in treatment of severe intoxi- 
cation. Although the rate of metabolism of alcohol 
varies with many circumstances, the average may 
be about 10 Gm. per hour. The caloric sig- 
nificance of alcohol may be illustrated by noting 
that the ingestion of 1 pint of whisky in 24 hours 
could result in the combustion of 170 Gm. of 
alcohol and the production of 1,200 Calories, 
which represents the basal caloric requirement of 
a good-sized man. If his food consumption de- 
creases accordingly, avitaminosis and other evi- 
dences of malnutrition result; if food consump- 
tion continues, obesity results. Usual concentra- 
tions do not seem to effect liver function, but 
Newman et al. (J. Pharmacol., 1940, 168, 194) 
found decreased liver glycogen, increased blood 
lactic acid and decreased hepatic oxygen con- 
sumption following high concentrations of alcohol 
in the blood. A low normal sulfobromophthalein 
clearance was reported in chronic alcoholics with- 
out obvious liver disease (Goodman and Kings- 
ley, J.A.M.A., 1953, 153, 462). 

Gastrointestinal. — Alcohol has a marked in- 
fluence on gastric and probably also intestinal 
digestion. As a carminative in flatulent dyspepsia, 
alcoholic beverages or alcoholic solutions of essen- 
tial oils (tinctures) are commonly used with 
symptomatic benefit. 

Dilute alcohol solutions stimulate gastric secre- 
tion; 50 ml. of 7 per cent alcohol is commonly 
used as a test meal in lieu of the classical tea-and- 
toast meal and has the advantage of containing 
no particulate matter to block the aspirating tube. 
Roth et al. (J.A.M.A., 1944, 126, 814) reported 
that the alcohol test meal caused a greater rise 
in free hydrochloric acid in patients with peptic 
ulcer than in normal persons. Concentrations up 
to 10 per cent produce a gastric juice rich in 
hydrochloric acid although poor in pepsin (Bloom- 
field and Keefer, J. Clin. Inv., 1928, 5, 295). 
Concentrations of 20 to 40 per cent alcohol or 
more cause inflammation of the gastric mucosa 



38 



Alcohol 



Part I 



(Beazell and Ivy, Quart. J. Stud. Alcohol, 1940, 
1, 45). After section of the vagi or their paralysis 
by atropine this increase in the digestive secre- 
tions does not occur. (For further information 
on the effects of alcohol on digestion, see Gray, 
Am. J. Physiol, 1937, 120, 657.) It has been 
shown by Greenberg, Lolli, and Rubin {Quart. J. 
Stud. Alcohol, 1942, 3, 371) that intravenously 
administered alcohol delays the emptying time 
of the stomach. 

Skin. — Alcohol is widely used for application 
to the skin. It serves as an irritant, an anhidrotic. 
and an astringent by virtue of its precipitation of 
cellular protein, thus being useful in the hygienic 
care of the skin in bed-ridden patients and the 
prevention of decubitus ulcers. Its cooling quality 
on evaporation is well known in the nursing care 
of febrile patients. It may be used to remove 
phenol, poison ivy, etc., from the skin. There is 
no more widely used antiseptic for the skin in 
preparation for surgical procedures, as well as in 
the disinfection of surgical instruments. Price 
(Arch. Surg., 1950, 60, 492) reported that a 
2-minute washing of the surgeon's hands in 70 to 
95 per cent alcohol decreased the surviving bac- 
terial flora to less than 10 per cent. Lesser con- 
centrations were less effective. Some bacterial 
spores are resistant to alcohol. Heat sterilization 
is necessary for surgical instruments. Further- 
more, storage in alcohol results in rusting of steel 
instruments. Price (J.A.M.A., 1944, 124, 189) 
recommended its use locally for the treatment of 
furunculosis. For intractable pulmonary edema, 
Gootnick et al. (New Eng. J. Med., 1951, 245, 
842) and Luisada et al. (Circulation, 1952, 5, 
363) nebuilized 50 per cent alcohol and caused 
its inhalation with oxygen pressure in a meter 
mask. The alcohol has an antifoaming action, 
causing the fine bubbles in the smaller bronchi 
to collapse and permit entry of the oxygen. 

Xerve Block. — Alcohol is used by injection 
for intractable pain, as in trigeminal neuralgia 
(tic douloureux) (Sweet, J.A.M.A., 1950, 142, 
392), angina pectoris (Levy and Moore, J. A.M. A., 
1941, 116, 2563), inoperable cancer of the pelvis, 
and in sciatica. 

In the management of intractable pain in the 
pelvis or legs, 0.75 ml. of absolute or 95 per cent 
alcohol is injected slowly over a period of 2 min- 
utes through a lumbar puncture needle in the 
fourth lumbar interspace with the patient lying 
on the side opposite to that with the most pain. 
The patient must remain in this lateral recumbent 
position for 2 hours. The specific gravity of the 
alcohol is less than that of the spinal fluid and 
the alcohol in this lateral recumbent position 
rises into contact with the posterior spinal roots. 
Spinal fluid should not be withdrawn to mix with 
the alcohol in the syringe. If needed the injection 
may be repeated for the other side a week or two 
later. Considerable neuritic pain may follow this 
injection for 1 to 2 weeks and in some instances 
the motor nerves may be damaged by the alcohol. 
This procedure is indicated only for severe pain 
in metastatic carcinoma or other hopeless condi- 
tion (Bonica, /. Michigan M. Soc, 1953, 52, 
284) because of the arachnoiditis, and damage to 
the spinal cord it produces. 



Stellar (Arch. Neurol. Psychiat., 1953, 69, 
343) used subarachnoid injections of alcohol to 
relieve spasticity and contractures in paraplegic 
patients. 

Retrobulbar injections of alcohol for painful 
eyes which cannot be enucleated surgically for 
some reason gave relief for several months and 
did not permanently destroy remaining visual 
ability (Maumenee, Am. J. Ophth., 1949, 32, 
1502). 

In prolonged, severe pain, alcohol injections 
have been employed to destroy temporarily the 
peripheral nerve from the involved area. This 
has been done with the intercostal nerves in in- 
stances of tuberculous or other chronic form of 
pleurisy. Klein (Wien. klin. Wchnschr., 1949, 99, 
512) reported successful use of alcohol injections 
of the sympathetic nerve chain at the fifth and 
tenth thoracic vertebral levels in lieu of sympa- 
thectomy in cases of severe hypertension. 

For intractable pruritus vulvae, Wilson (West. 
J. Surg. Obst. Gynec, 1949, 57, 406) made multi- 
ple subcutaneous injections of 0.1 to 0.25 ml., 
spaced about 1 to 2 cm. apart, with relief in about 
half of the cases. 

Anesthesia. — Intravenous alcohol anesthesia 
was reported by Verkhovskaya (Am. Rev. Soviet 
Med., 1945, 2, 260). His patients in an evacua- 
tion hospital were prepared as for ether anesthesia. 
The solution used is one part 95 per cent alcohol 
with two parts of 5 per cent dextrose solution, 
the average amount for narcosis being 2 to 2.5 ml. 
per Kg. body weight. For example, a 60 Kg. 
patient needs 120 ml. of alcohol and 240 ml. of 
dextrose solution. The infusion is given slowly 
over 15 or 20 minutes until the patient sleeps. 
After deep anesthesia is present the vein is flushed 
with 30 to 40 ml. of normal saline to prevent 
thrombo-phlebitis. Sleep lasts two to five hours. 
The dose is more difficult to regulate than with 
ether by inhalation and the reflexes are less well 
depressed than with ether. The prolonged re- 
covery period is often undesirable. 

Child (Ar. Y. State J. Med., 1951, 51, 1521) 
found this solution, with added vitamins, useful 
in the management of the withdrawal syndrome 
of opium addicts. 

Chapman and Williams (Am. J. Obst. Gyn., 
1951, 61, 676) used 7.5 per cent alcohol in 5 per 
cent dextrose injection intravenously for ob- 
stetrical analgesia, along with otherwise ineffective 
doses of meperidine, successfully except for vomit- 
ing in some cases and the difficulty of keeping 
the needle in the vein. Determinations of alcohol 
in the cord blood showed that alcohol reached 
the fetus, but depression of respiration was not 
observed. 

In status asthmaticus in children, 5 per cent 
ethyl alcohol in 5 per cent dextrose in isotonic 
sodium chloride solution or distilled water for 
injection has been employed in a dose of 40 ml. 
per kilogram of body weight; the first 80 to 100 
ml. is given in a period of 10 minutes and the 
remainder of the dose at a rate of 2 drops per 
kilogram per minute (Bacal and Pedvis, Can. 
Med. Assoc. J., 1948, 59, 410). In the control of 
intractable pain, 5 or 10 per cent alcohol in 5 per 
cent dextrose may be given intravenously; relief 



Part I 



Alcohol 



39 



is transient and the resulting inebriation may be 
unpleasant. 

For postspinal-puncture headache, which is 
often totally disabling and resistant to therapy, 
Deutsch (Anesth., 1952, 13, 496) gave 1 liter of 
5 per cent alcohol in 5 per cent dextrose injection 
intravenously over a period of 4 hours with relief 
in 10 of 15 cases. 

Parenteral Nutrition. — Rasmussen (Jackson 
Clin. Bull., 1945, 7, 45) recommended intravenous 
alcohol as supportive treatment postoperatively, 
administering 1 to 3 liters of 5 to 10 per cent 
solution in 5 per cent dextrose and saline solution. 
Alcohol may be administered intravenously to 
adults at a rate up to 15 ml. per hour without 
causing significant inebriation. In addition to some 
sedative action, it has nutritional value in the fre- 
quently malnourished postoperative case (Karp 
and Sokol, J.A.M.A., 1951, 146, 21). Pending 
the availability of stable fat emulsions for in- 
travenous injection to supply calories in sufficient 
quantity to spare protein tissue from combustion 
for the daily caloric requirement such an alcohol- 
saline-dextrose mixture with 5 per cent protein 
hydrolysate is useful (Rice et al., J. -Lancet, 1948, 
78, 91) ; the alcohol provides 7 Calories per gram. 
In malnourished individuals, it is important to 
add therapeutic doses of the B-vitamins to this 
solution to avoid precipitation of the enceph- 
alopathy of Wernicke with the large dose of 
carbohydrate. 

Stimulant. — As a circulatory stimulant there 
is no doubt that in the past too much confidence 
has been placed in alcohol. Nevertheless, if used 
circumspectly, it is often of value. Myers 
(/. Pharmacol, 1933, 49, 483), in studying the 
treatment of the shock produced by diphtheria 
toxin, found that alcohol was the only drug of 
those he tested which caused a definite improve- 
ment in the circulation. It is used especially when 
it is desired to tide the patient over for a limited 
period of time. It must never be forgotten that 
large doses are depressant. While a small amount 
of alcohol may prove useful in cases of snake bite, 
it is no exaggeration to say that the injudicious 
exhibition of this drug has been responsible for 
many deaths after rattlesnake bites, where the 
specific antivenin would have been life-saving. 
In the circulatory failure due to anesthetics it 
should be sedulously avoided; on account of its 
close chemical relation to both ether and chloro- 
form it acts as a synergist rather than an antag- 
onist to these poisons. The use of alcohol in 
infectious fevers, especially typhoid fever, in- 
volves a large number of factors concerning some 
of which we have at present no definite knowledge. 
The impairment of digestion, which is so uni- 
versal an accompaniment of these diseases, sug- 
gests the use of alcohol both as a stimulant to 
gastric secretion and as an accessory food. While 
febrile patients are capable of burning up larger 
quantities of alcohol than normal individuals, if 
given too freely the unoxidized alcohol circulat- 
ing in the blood may prove injurious. An alco- 
holic odor to the breath is generally a sign that 
the patient is receiving more than he can oxidize. 
Many believe that the mild narcotic action of 



alcohol is also of service in preserving the vitality 
in these adynamic states. 

Taken internally, alcohol tends to increase the 
sweat by dilating the vessels of the skin and is 
frequently used as an aid to more powerful 
diaphoretic measures in the abortion of mild in- 
fections, such as acute coryza. 

In dysmenorrhea, alcoholic beverages are often 
an effective analgesic but the general action is 
undesirable in this recurrent condition. 

In insomnia, particularly in older people, an 
alcoholic beverage at bedtime may be most effec- 
tive in bringing relaxation and sleep; for this 
purpose the dose should not exceed 10 to 20 ml. 
of whisky, lest excitement rather than sedation be 
produced. Alcohol relaxes athetosis but it is hardly 
possible to use it in the treatment of this chronic 
disorder. 

Raw alcohol is rarely used internally, prefer- 
ence being shown for one of the alcoholic bever- 
ages, such as whisky, brandy, or wine. 

Pharmaceutical Uses. — Various strengths of 
alcohol are used in pharmacy, as for preservation 
of a variety of medicinals, extraction of active 
principles of crude drugs, and for dissolving sub- 
stances which are more soluble in hydroalcoholic 
media than they are in water. IYJ 

Toxicology. — The symptoms of acute alcohol 
poisoning are unfortunately so widely known that 
detailed description is unnecessary, but alcohol 
poisoning is of great importance, not alone be- 
cause of the frequency of serious results, but be- 
cause of the similarity of its symptoms with those 
of certain diseases or other narcotic poisons. The 
odor of paraldehyde on the breath may be mis- 
taken for alcohol. Barbiturate poisoning, skull 
fracture, cerebral hemorrhage or schizophrenia 
may simulate alcoholism. The important diag- 
nostic symptoms are the characteristic odor on 
the breath and the peculiar maudlin mentality, if 
the patient can be aroused. Nystagmus, clumsy 
performance of coordinated movements, such as 
walking a straight line, and impaired perception 
of fine differences are characteristic. In the coma- 
tose state the pupils are usually somewhat dilated, 
the face is flushed, the skin is cold and moist, the 
pulse is rapid and the breathing noisy and re- 
duced in frequency. The fatal dose of whisky 
requires the ingestion of 1 quart within a few 
minutes, which seldom occurs because of incoordi- 
nation and pylorospasm. 

The treatment of alcohol poisoning consists in 
the immediate evacuation of the stomach, main- 
tenance of body temperature by use of external 
heat, and use of respiratory stimulants, notably 
caffeine and sodium benzoate or enemas of strong 
coffee. Inhalation of aromatic ammonia spirit 
may arouse temporarily. Carbon dioxide (5 per 
cent) and oxygen (95 per cent) inhalations are 
required in profound coma. Apomorphine solu- 
tion is often injected but in an alcoholic patient 
it may produce still further depression rather than 
initiating vomiting. Ephedrine or amphetamine 
may be helpful. 

Habitual alcoholism is a major health and eco- 
nomic problem. More is spent annually on alco- 
holic beverages than on health. Block (GP, Sept. 
1952) estimated the cost of the effects of alco- 



40 



Alcohol 



Part I 



holism to exceed a half billion dollars yearly; 20 
million by private and another 20 million by 
public agencies in the care of the families of 
problem drinkers, 30 million for the care of alco- 
holics in mental hospitals, 25 million for the care 
of alcoholic prisoners in jails, 125 million expense 
of preventable accidents due to alcohol, and over 
a half billion in loss of productivity in industry 
due to alcoholism. About half of all chronic alco- 
holics have an underlying mental disorder. The 
other half, commencing as "social drinkers," 
enjoy the escape from the frustrations of life and 
by virtue of frequent excessive indulgence become 
less able to cope with their problems and sink into 
the results of chronic alcoholism. Gastritis is not 
infrequent. Alcoholism is present in most cases 
of cirrhosis of the liver but the relation is not one 
of a toxic effect of alcohol on the liver. Malnutri- 
tion secondary to a failure to eat an adequate 
diet is important. The glucose tolerance may be 
altered (see Voegtlin, Quart. J. Stud. Alcohol, 
1943, 4, 163). Dewan (Am. J. Psychiat., 1943, 
99, 565) indicates that riboflavin and niacin are 
components of the oxidation mechanism of alcohol 
within the brain substance, this mechanism acting 
as a hydrogen carrier between reduced diphospho- 
pyridine nucleotide and the cytochrome system. 
Spies and Aring (J. A.M. A., 1938, 110, 1081) 
snowed that "alcoholic polyneuritis" could be 
cured by correcting the malnutrition without dis- 
continuing the alcohol intake. Emaciation and 
general ill health in the alcoholic seems to be 
due to malnutrition. The red nose and the acne- 
form skin lesions may be related to ariboflavinosis. 
Korsakoff's psychosis described in chronic alco- 
holics resembles the mental aberration seen in 
pellagra. Wernicke's syndrome is related to a 
deficiency of vitamin B. 

Figueroa et al. (J. Clin. Nutrition, 1953, 1, 
179) comment on the low incidence of frank 
avitaminosis in chronic alcoholics at the present 
time in contrast to the higher incidence in the 
past. 

Delirium tremens is characterized by an acute 
panic, excitement and fear, visual and auditory 
hallucinations and marked exhaustion. It may be 
precipitated in the chronic alcoholic by inter- 
current disease, sudden withdrawal of alcohol or 
an increased consumption of alcohol. Cerebral 
edema is often present and may cause death. 
Alcohol tends to cause an increase in extracellular 
fluid. Alcoholics are seriously ill and require care- 
ful supportive therapy. Much folklore concerns 
the increased tolerance of the chronic drinker to 
alcohol but the increased consumption never ap- 
proaches the magnitude of the morphine addict. 
Schweisheimer {Deutsch. Arch. f. klin. Med., 
1912-3. 109, 271) showed that the non-drinker 
reacted much more violently to a given concen- 
tration of alcohol in the blood than did the 
habitual consumer of alcoholic beverages. Animal 
studies by Newman and Lehman (/. Pharmacol., 
1938, 62, 301) showed that symptoms appeared 
in habituated animals only at higher concentra- 
tions in the blood than in previously unexposed 
animals; since the brain in these habituated ani- 
mals was equally permeable to the alcohol, it was 
suggested that the cells had become resistant to 



the effects of the lower concentration. At the 
most this increased tolerance is not more than 
2 or 3 times that of the unexposed individual. 
The resistance of chronic alcoholics to the related 
anesthetics such as ether and chloroform is com- 
patible with such an explanation. 

The management of the chronic alcoholic is 
initially protective and supportive until malnutri- 
tion can be corrected and health restored. Defini- 
tive treatment is psychiatric in nature and has 
been most successful under the auspices of such 
organizations as Alcoholics Anonymous, in which 
group psychotherapy and occupational therapy 
are conducted by individuals who themselves 
have recovered from chronic alcoholism. This 
voluntary approach has been the most successful, 
particularly in the older individual with previous 
skills and with family obligations. It is unfortu- 
nate that the individual must often be hurt so 
badly before he voluntarily associates himself 
with such a group, but the desire to reform is 
essential to the discontinuance of alcohol. As 
already noted delirium tremens requires expert 
medical care. The former practice of lumbar 
puncture to withdraw spinal fluid to relieve pres- 
sure resulted in many fatalities, perhaps as a re- 
sult of herniation of the brain stem through the 
foramen magnum; the use of magnesium sulfate 
by mouth or, in emergencies, 50 per cent dextrose 
intravenously is effective and safer. Smith 
(J.A.M.A., 1953, 152, 384) recommended the 
following regimen: hospitalize under careful nurs- 
ing care; inject 1 liter of 5 per cent dextrose in 
isotonic sodium chloride solution (for injection) 
containing 500 mg. ascorbic acid, 200 mg. thia- 
mine hydrochloride and 100 mg. nicotinamide 
intravenously and repeat in 12 hours; give paral- 
dehyde 10 to 16 ml. or chloral hydrate 1 to 2 
Gm. by mouth as often as needed to control 
delirium and mephobarbital 200 mg. four times 
daily by mouth. Feldman and Zucker (J.A.M.A., 
1953, 153, 895) confirmed the value of adrenal 
cortical extract to shorten convalescence (see 
under Adrenal Cortex Injection). Under sanato- 
rium control, the use of alcoholic beverages along 
with nauseants, such as ipecac or apomorphine 
(Feldman, Praxis, 1952, 41, 871), may be useful 
but cannot substitute for the determination of the 
individual to discontinue use of alcohol com- 
pletely. The use of tetraethylthiuram disulfide 
(see in Part II), which causes intense discomfort 
if alcohol is ingested, may be useful in the same 
way as the nauseants. 

Because of the medicolegal importance in auto- 
mobile accidents resulting from driving while 
intoxicated, and also in the investigation of violent 
deaths (Wilentz, Am. Pract. Dig. Treat., 1953, 4, 
21), tests of alcohol levels in blood and urine are 
of great importance. A useful quantitative test is 
described in Levinson and MacFate's Clinical 
Laboratory Diagnosis, 4th Edition, 1951; in this 
test alcohol is quantitatively oxidized to acetic 
acid by a standard potassium dichromate solution 
used in excess, the excess of the latter being de- 
termined through liberation of iodine from potas- 
sium iodide and titration with standard sodium 
thiosulfate solution. The National Safety Coun- 
cil (Progress Report of the Committee on Tests 



Part I 



Alcohol, Diluted 41 



for Intoxication of the Street and Highway Traffic 
Section, 1937) recommended that a blood concen- 
tration of more than 0.15 per cent is conclusive 
evidence of intoxication; levels of 0.05 per cent 
to 0.15 per cent may be associated with mild 
intoxication, which must be evaluated by tests 
of psychomotor performance; if the level is less 
than 0.05 per cent the driver should not be 
prosecuted (Newman, /. Clin. Psychopath., 
1946-7, 8, 83). Alcohol should not be applied to 
the skin before taking blood samples. Sodium 
fluoride (500 mg. for a blood specimen of 3 to 6 
ml.) will serve as an anticoagulant and preserva- 
tive of the alcohol for many hours if analysis 
must be delayed. An alcoholmeter for simple and 
almost automatic estimation of alcohol in expired 
air was developed by Greenberg and Keator 
(Quart. J. Stud. Alcohol, 1941-2, 2, 57) for use 
by trained, nonmedical personnel in police de- 
partments. In this apparatus the alcohol in the 
breath reacts with pentoxide and in turn pro- 
duces a starch-iodine blue color which is recorded 
by a photoelectric cell. 

Storage. — Preserve "in tight containers, re- 
mote from fire." U.S.P. 

DEHYDRATED ALCOHOL. N.F. (LP.) 

Dehydrated Ethanol, "Absolute Alcohol" [Alcohol 
Dehydratum] 

"Dehydrated Alcohol contains not less than 
99 per cent by weight of C2H6O." N.F. The LP. 
Absolute Ethanol is ethyl alcohol with not more 
than 2 per cent w/w of water; not less than 98.8 
per cent v/v, corresponding to not less than 98.1 
per cent w/w, of C2H5OH is required. 

Alcohol Absolutus; Alcohol Ethylicum; Spiritus Abso- 
lutus. Fr. Alcool ethylique; Ethanol; Alcool absolu; Alcool 
a cent degres centesimaux. Ger. Absoluter Alkohol. It. 
Alcool etilico assoluto. Sp. Alcohol absoluto; Alcohol 
deshidratado. 

The term "absolute alcohol" is properly applied 
only to 100 per cent C2H5OH; the correct desig- 
nation for a liquid containing over 99 per cent, 
but less than 100 per cent, of C2H5OH, is de- 
hydrated alcohol. 

As mentioned previously, the maximum concen- 
tration of C2H5OH obtainable by the regular 
methods of fractional distillation is 95.57 per 
cent, corresponding to the composition of the 
constant-boiling mixture of alcohol and water. 
By azeotropic distillation in which a third compo- 
nent, such as benzene, is present, it is possible to 
prepare even absolute alcohol. The process de- 
pends on the fact that when a mixture of ordinary 
alcohol and benzene is distilled the initial frac- 
tion, passing over at 64.8°, contains benzene, 
water and alcohol; the second fraction, distilling 
at 68.2°, is composed of benzene and alcohol; the 
third, boiling at 78.3°, is absolute alcohol. This is 
the commercial process for preparing dehydrated 
alcohol. A similar use of ether as an entraining 
agent has been proposed. 

Prior to the use of the azeotropic distillation 
process, dehydrated alcohol was prepared by add- 
ing to alcohol various substances which possess 
an affinity for water. The British Pharmacopoeia 
of 1895 directed that alcohol be kept in contact 
with anhydrous potassium carbonate during 24 



hours, decanted, then allowed to stand in contact 
with fused calcium chloride for a like period, and 
finally distilled from the latter. Other drying 
agents which have been used, and still are em- 
ployed in laboratory preparation of dehydrated 
alcohol, are freshly calcined lime, anhydrous 
potassium and sodium acetates, barium oxide, and 
metallic calcium, which last reacts with water to 
form calcium hydroxide. 

Description and Tests. — "Dehydrated Al- 
cohol is a transparent, colorless, mobile, and vola- 
tile liquid, having a characteristic odor, and a 
burning taste. It is hygroscopic and flammable. 
Dehydrated Alcohol is readily volatilized even at 
low temperatures and boils at about 78°. Dehy- 
drated Alcohol is miscible with water without any 
trace of cloudiness. It is also miscible with ether 
and with chloroform. The specific gravity of 
Dehydrated Alcohol is not more than 0.798 at 
15.56° (the U. S. Government standard tempera- 
ture for Alcohol)." N.F. 

The N.F. prescribes the same tests for this 
liquid as does the U.S.P. for alcohol and, in 
addition, requires that dehydrated alcohol meet 
the requirements of the tests for alkaloids and 
formaldehyde under Whisky. 

Absolute (100 per cent) alcohol has a specific 
gravity, at 15.56°, of 0.7936. 

The tests frequently employed to prove the 
absence of water by dropping into dehydrated 
alcohol anhydrous barium oxide or anhydrous 
copper sulfate are not reliable, as Squibb demon- 
strated that when one-half of one per cent of 
water is added to absolute alcohol no change in 
either the barium oxide or the anhydrous copper 
sulfate took place. Gorgeu's test of forming a clear 
solution when mixed with an equal bulk of pure 
benzene is more delicate. The test of Henle (Ber., 
1920, 53, 719) is capable of detecting 0.05 per 
cent of water in ethyl alcohol; in this test a solu- 
tion of aluminum ethoxide in benzene forms a 
voluminous precipitate when added to ethyl al- 
cohol containing water. 

Uses. — Dehydrated alcohol is sometimes in- 
jected into the immediate neighborhood of nerve 
ganglia, or even into the spinal cord, for the 
relief of pain (see also under Alcohol). It is used 
as a reagent in certain tests, as a solvent in sys- 
tems where water must be excluded, and in certain 
syntheses. 

Storage. — Preserve "in tight containers, re- 
mote from fire." N.F. 

DILUTED ALCOHOL. U.S.P. 

Diluted Ethanol, [Alcohol Dilutum] 

"Diluted Alcohol is a mixture of alcohol and 
water containing not less than 41 per cent and 
not more than 42 per cent by weight, correspond- 
ing to not less than 48.4 per cent and not more 
than 49.5 per cent by volume, at 15.56°, of 
C2H5OH." U.S.P. 

The B.P. does not use the title Diluted Alcohol, 
but gives a series of eight formulas for prepara- 
tion of Dilute Alcohols ranging from 20 per cent 
to 90 per cent, by volume. These are prescribed 
by specifying the concentration desired as, for 
example, "Alcohol (70 per cent)." 



42 Alcohol, Diluted 



Part I 



The I. P. Dilute Et Hanoi contains not less than 
69.1 per cent v/v and not more than 71 per cent 
v/v, corresponding to not less than 61.5 per cent 
w/w and not more than 63.5 per cent w/w, of 
CMoOH. 

Sp. Alcohol Diluido. 

The U.S. P. indicates that diluted alcohol may 
be prepared by mixing equal volumes of alcohol 
and purihed water, both measured at the same 
temperature. At 25° the contraction in volume, 
after cooling the mixture to the same tempera- 
ture, is about 3 per cent. 

Description and Tests. — "Diluted Alcohol 
is a transparent, colorless, mobile liquid, having a 
characteristic odor and a burning taste. The spe- 
cific gravity of Diluted Alcohol is not less than 
0.935 and not more than 0.937 at 15. 56°, indicat- 
ing not less than 41 per cent and not more than 
42 per cent by weight, or not less than 48.4 per 
cent and not more than 49.5 per cent by volume, 
of C2H5OH. In other respects Diluted Alcohol 
complies with the tests under Alcohol, allowance 
being made for the difference in alcohol concen- 
tration." U.S.P. 

Uses. — Diluted alcohol is employed chiefly as 
a menstruum and solvent in various pharmaceu- 
tical manufacturing processes. When the thera- 
peutic effects of alcohol are desired it is cus- 
tomary to employ either whisky or brandy. For 
description of the physiologic and therapeutic 
properties, see under Alcohol. 

Storage. — Preserve "in tight containers, re- 
mote from fire." U.S.P. 

ALCOHOL RUBBING COMPOUND. 

N.F. 

Rubbing Alcohol, [Alcohol Fricamentum Compositum] 

"Alcohol Rubbing Compound and all prepara- 
tions coming under the classification of Rubbing 
Alcohols must be manufactured in accordance 
with the requirements of the Internal Revenue 
Service, U. S. Treasury Department, using spe- 
cially denatured alcohol Formula 23-G (3.5 parts 
by volume of methyl propyl ketone, 0.5 part by 
volume of methyl isobutyl ketone, and 100 parts 
by volume of ethyl alcohol), or Formula 23-H 
(8 parts by volume of acetone, 1.5 parts by vol- 
ume of methyl isobutyl ketone, and 100 parts by 
volume of ethyl alcohol). It contains not less than 
68.5 per cent and not more than 71.5 per cent by 
volume of absolute ethyl alcohol. Alcohol Rubbing 
Compound contains in each 100 ml. not less than 
355 mg. of sucrose octaacetate. Small quantities of 
perfume oils may be added if desired. The prep- 
aration may also be colored with one or more 
coal-tar colors, certified by the Food and Drug 
Administration for use in drugs. A suitable stabi- 
lizer may also be added. Alcohol Rubbing Com- 
pound complies with the requirements of the In- 
ternal Revenue Service of the United States 
Treasury Department. Note: Alcohol Rubbing 
Compound must be packaged, labeled and sold in 
accordance with the regulations issued by the 
Internal Revenue Service, U. S. Treasury De- 
partment." N.F. 

Description. — "Alcohol Rubbing Compound 



is a transparent, colorless or colored as desired, 
mobile, and volatile liquid. It has an extremely 
bitter taste, and in the absence of added odorous 
constituents, a characteristic odor. It is flammable. 
The specific gravity of Alcohol Rubbing Com- 
pound, manufactured with specially denatured 
alcohol Formula 23-G, is not less than 0.8797 and 
not more than 0.8874, and the specific gravity of 
Alcohol Rubbing Compound, manufactured with 
specially denatured alcohol Formula 23-H is not 
less than 0.8691 and not more than 0.8771 at 
15.56° (the U. S. Government standard tempera- 
ture for alcohol j." N.F. 

Standards and Tests. — Non-volatile residue. 
— The weight of residue obtained by evaporating 
25 ml. of alcohol rubbing compound and drying 
the residue at 105° for 1 hour is not less than 
89 mg. Methanol. — 0.5 ml. of a dilution of 0.5 ml. 
of alcohol rubbing compound to 1 ml. with water 
meets the requirements of the test for methanol 
under Whisky. Assay for sucrose octaacetate. — 
The residue from the test for non-volatile residue 
is neutralized with 0.1 N sodium hydroxide, using 
phenolphthalein T.S., and then saponified by heat- 
ing with a measured excess of 0.1 N sodium hy- 
droxide. The excess alkali is titrated with 0.1 N 
sulfuric acid. Each ml. of 0.1 N sodium hydroxide 
represents 8.482 mg. of sucrose octaacetate (the 
equivalent is based on the formation of 8 mole- 
cules of acetic acid by hydrolysis). N.F. 

For a discussion of the use of alcohol exter- 
nally as a "rubbing compound" see under Al- 
cohol. The N.F. rubbing alcohol has been ren- 
dered unfit for beverage use and is. accordingly, 
available at a much lower cost to the consumer 
because it is not subject to the regular alcohol 
tax. Under no circumstances should Alcohol Rub- 
bing Compound be employed in place of alcohol. 

Storage. — Preserve "in tight containers, re- 
mote from fire." N.F. 

ALLYLBARBITURIC ACID. N.F. 

Allylisobutylbarbituric Acid 



CH 2 CH=CH 2 




CHCH(CH ) 
2 32 



Sandoptal (Sando:). 



Allylbarbituric acid, more informatively desig- 
nated 5-allyl-5-isobutylbarbituric acid, may be 
prepared by the method described by Yolwiler 
(J.A.C.S., 1925, 47, 2236) in which the diethyl 
ester of mono-isobutylmalonic acid is condensed 
with urea, producing mono-isobutylbarbituric acid, 
into which is introduced the allyl substituent by 
interaction with allyl bromide in sodium hydroxide 
solution. Acidification of the reaction mixture pre- 
cipitates the 5-allyl-5-isobutylbarbituric acid. 

Description. — "Allylbarbituric Acid occurs as 
a white, crystalline, odorless powder, with a 
slightly bitter taste. It is stable in air. A saturated 
solution is acid to litmus paper. Allylbarbituric 
Acid is freely soluble in alcohol, in ether, and in 
chloroform ; it is slightly soluble in cold water and 
soluble in boiling water. It is soluble in solutions 



Part I 



Almond Oil, Bitter 43 






of fixed alkalies and carbonates. Allylbarbituric 
Acid melts between 138° and 139°." N.F. 

Standards and Tests. — Identification. — (1) 
A filtered solution of 300 mg. of allylbarbituric 
acid in a mixture of 1 ml. of 1 N sodium hydrox- 
ide and 5 ml. of water is divided into two por- 
tions: one portion yields with 1 ml. of mercury 
bichloride T.S. a white precipitate, soluble in 10 
ml. of ammonia T.S.; the other portion yields 
with 5 ml. of silver nitrate T.S. a white precipi- 
tate, soluble in 5 ml. of diluted ammonia solu- 
tion. (2) On boiling 500 mg. of the acid with 
5 ml. of 1 in 4 sodium hydroxide solution am- 
monia is evolved. (3) A saturated solution of 
allylbarbituric acid in water is prepared: on add- 
ing 1 ml. of acetic acid and 0.5 ml. of bromine 
T.S. to 5 ml. of the solution the bromine color is 
discharged immediately; on adding 0.1 ml. of 
potassium permanganate T.S. to another 5 ml. 
portion of the solution a yellow color appears im- 
mediately, turning to brown. Loss on drying. — 
Not over 1 per cent, when dried at 105° for 2 
hours. Residue on ignition. — Not over 0.1 per 
cent. Heavy metals. — About 100 mg. of allyl- 
barbituric acid is boiled with 10 ml. of water for 
2 minutes, cooled, and filtered: on saturating the 
filtrate with hydrogen sulfide no coloration or pre- 
cipitation results. Readily carbonizable substances. 
— A solution of 500 mg. of the allylbarbituric 
acid in 5 ml. of sulfuric acid has no more color 
than matching fluid A. N.F. 

Uses. — Allylbarbituric acid (see article on 
Barbiturates, in Part II, for general discussion) 
has been classified as being a barbiturate of inter- 
mediate duration of action, according to the sys- 
tem of Fitch and Tatum (/. Pharmacol., 1932, 
44, 325). Its duration of action is of an order 
comparable with that of aprobarbital and of amo- 
barbital (Tatum, Physiol. Rev., 1939, 19, 472). 
In general, it is employed as an hypnotic agent 
or for mild sustained sedation. In this respect its 
clinical indications are much the same as for bar- 
bital or amobarbital. 

Allylbarbituric acid is metabolized primarily 
in the liver, according to Masson and Beland 
(Anesth., 1945, 6, 483). Only trace amounts are 
excreted as such by normal patients (Koppanyi 
et al., J. Pharmacol., 1934, 52, 87). Staub re- 
ported that some 20 per cent of the daily dose 
administered to schizophrenic patients was ex- 
creted as such (Schweiz. Arch. Neurol. Psychiat., 
1950, 65, 330). Allylbarbituric acid apparently 
possesses no toxicologic characteristics that are 
not shared on a pharmacodynamic basis with other 
barbiturates. Nielsen et al. (J. Pharmacol., 1925, 
26, 371) found that the minimum lethal dose of 
allylbarbituric acid, when the sodium salt was in- 
jected subcutaneously into white rats, was 175 
mg. per Kg. of body weight, with the ratio of 
minimum effective dose to minimum lethal dose 
being next to the most favorable for the series of 
15 barbiturates which they investigated. 

Dose. — For sedation the dose range is 100 to 
200 mg. (approximately l/ 2 to 3 grains); the 
hypnotic dose varies from 200 to 800 mg., the 
higher doses being used in obstinate cases of 
insomnia. 



Storage. — Preserve "in well-closed contain- 
ers." N.F. 

ALLYLBARBITURIC ACID 
TABLETS. N.F. 

"Allylbarbituric Acid Tablets contain not less 
than 94 per cent and not more than 106 per cent 
of the labeled amount of C11H16N2O3." N.F. 

The assay is identical with that described under 
Barbital Tablets. 

Usual Size. — 200 mg. (approximately 3 
grains). 



BITTER ALMOND OIL. 

[Oleum Amygdalae Amarae] 



N.F. 



"Bitter Almond Oil is the volatile oil obtained 
from the dried ripe kernel (deprived of fixed oil) 
of Primus Amygdalus Batsch var. amara (De 
Candolle) Focke (Fam. Rosacea), or from other 
kernels containing amygdalin, by maceration with 
water and subsequent distillation with steam. It 
contains not less than 80 per cent of CgHs.CHO, 
and not less than 2 per cent and not more than 4 
per cent of HCN. Bitter Almond Oil in which 
crystals have formed must not be dispensed. 

''Caution. — Bitter Almond Oil is intended for 
medicinal use and neither it nor its solution should 
be used or sold for flavoring foods." N.F. 

This should not be confused with the B.P. 
Volatile Bitter Almond Oil, which contains no 
hydrocyanic acid. 

Oil of Bitter Almond. Oleum Amygdalarum Amararum 
^Ethereum. Fr. Essence d'amande amere. Ger. Atherisches 
Bittermandelol. Sp. Esencia de almendre amarga. 

The almond tree — Prunus Amygdalus Batsch 
(Amygdalus communis Linne) — resembles some- 
what the cherry. The leaves are elliptical, 
petiolate, minutely serrated, and are of a bright 
green color. The flowers are large, varying from 
pink to white, with very short peduncles, and 
petals longer than the calyx, and usually stand in 
pairs upon the branches. The fruit is a drupe with 
the outer covering thin, tough, dry, downy, and 
marked with a longitudinal furrow, where it opens 
when fully ripe. Within this covering is a rough 
shell, containing the kernel or almond. 

There are several varieties of this species of 
Prunus, differing chiefly in the size and shape of 
the fruit, the thickness of the shell, and the taste 
of the kernel. The two most important are the 
var. dulcis and the var. amara, the former bearing 
sweet, the latter bitter, almonds. Both of these 
varieties have been known since ancient times. 
The almond tree is a native of subtropical Asia 
and Asia Minor. It is now cultivated also in 
southern Europe, northern Africa, southern Eng- 
land, and California. Bitter almonds are chiefly 
imported from France, Morocco and Sicily. Bitter 
almond oil is usually imported from France, 
United Kingdom and Netherlands. In 1952 these 
countries shipped 3777 pounds to the United 
States. 

Bitter Almonds. — These seeds are smaller than 
the sweet almonds, which they resemble in gen- 
eral appearance, but are distinguished by being 
shorter and proportionally broader, by their bitter 
taste, and by the characteristic odor resembling 



44 Almond Oil, Bitter 



Part I 



that of hydrocyanic acid when they are bruised 
in a mortar and triturated with water. 

They have the bitter taste of the peach kernel, 
and, though when dry. are inodorous or nearly so, 
have, when triturated with water, the fragrance 
of peach blossom. They contain essentially the 
same constituents as sweet almonds, and like them 
form a milky emulsion with water. Their char- 
acteristic flavor is due to the formation of benz- 
aldehyde and hydrocyanic acid. These principles 
do not preexist in the almond, but result from 
the decomposition of the glycoside amygdalin. 
Amygdalin is mandelonitrile-p-gentiobioside, a 
glycoside of mandelonitrile, CoHsCHOHCN, with 
gentiobiose, a disaccharide formed by the conden- 
sation of two glucose molecules. It is white, crys- 
tallizable, inodorous, of a sweetish bitter taste, 
freely soluble in water and hot alcohol, very 
slightly soluble in cold alcohol, and insoluble in 
ether. It is hydrolyzed in the presence of diluted 
acids or the enzyme emulsin, which accompanies 
it in bitter almond. Destruction of emulsin, as by 
heating, prevents the hydrolysis of amygdalin 
and consequently of the development of the char- 
acteristic flavor of bitter almond. 

Mandelonitrile glucosides occur in three iso- 
meric forms: sambunigrin found in elder flowers, 
priilanrasin found in cherry laurel, and prunasin 
found in wild cherry bark. All of these are op- 
tically active, being levorotatory, but vary in 
the degree of rotation. According to Power and 
Moore {Trans. Chem. Soc, 1909, p. 243) they are 
combinations of dextro-, racemic and levo-man- 
delonitrile. respectively (see also Fischer and 
Bergmann, Ber., 1917, 50, 1047). 

Description. — "Bitter Almond Oil is a clear, 
colorless or yellow, strongly refractive liquid, hav- 
ing the characteristic odor and taste of benzalde- 
hyde. Bitter Almond Oil is slightly soluble in 
water. It is miscible with alcohol and with ether. 
Bitter Almond Oil is soluble in 2 volumes of 70 
per cent alcohol, forming a clear solution. The 
specific gravity of Bitter Almond Oil is not less 
than 1.05S and not more than 1.060 at 25V N.F 

Standards and Tests. — Optical rotation. — 
Bitter almond oil is optically inactive or does not 
have a rotation of more than +0.167° when de- 
termined in a 100-mm. tube at 25°. Refractive 
index. — Not less than 1.5410 nor more than 
1.5442 at 20°. Heavy metals. — The oil complies 
with the requirements of the official test for 
Heavy metals in volatile oils. Halogens. — No 
turbidity is produced when silver nitrate T.S. is 
added to products of the combustion of 3 or 4 
drops of bitter almond oil which have been con- 
densed on the moistened inside of an inverted 
beaker after the oil is ignited. Nitrobenzene. — 
No odor of phenyl isocyanide is apparent on 
heating bitter almond oil, in which any nitroben- 
zene that may be present has been reduced with 
nascent hydrogen to aniline, with chloroform and 
sodium hydroxide T. S. N.F. 

Nitrobenzene was at one time a frequent adul- 
terant of bitter almond oil. It may be detected 
by the test given above. 

Assay. — For benzaldehyde. — A sample of 
about 1 Gm. of the oil is reacted with a hydro- 
alcoholic solution of hydroxylamine hydrochloride, 



with which the benzaldehyde forms benzaldoxime 
and liberates a molecule of hydrogen chloride for 
each molecule of aldehyde present. The acid is 
titrated with 1 A 7 sodium hydroxide. After cor- 
recting for the acidity of the reagent each ml. of 
1 N sodium hydroxide is equivalent to 106.1 mg. 
of C-HoO. N.F. For hydrogen cyanide. — To some 
freshly prepared magnesium hydroxide suspension 
is added 1 Gm. of the oil, whereby the benzalde- 
hyde cyanhydrin releases cyanide ion which is 
titrated with 0.1 A 7 silver nitrate, using potassium 
chromate T.S. as indicator, until a permanent red 
coloration is produced. Any impurities in the 
magnesium hydroxide suspension which may react 
with silver nitrate are corrected for by titrating 
the suspension prior to addition of the oil. Each 
ml. of 0.1 N silver nitrate represents 2.703 mg. 
of HCN. N.F. 

Uses. — As benzaldehyde has no recognized 
medicinal action, bitter almond oil acts physio- 
logically like hydrocyanic acid. Death is said to 
have occurred in a man ten minutes after taking 
two fluidrachms of the oil. Bitter almond oil has 
been employed externally, dissolved in water in 
the proportion of one minim (0.06 ml.) to a fluid- 
ounce (30 ml.), in prurigo senilis and other cases 
of troublesome itching. To facilitate solution in 
water, the oil may be previously dissolved in alco- 
hol. Bitter almond oil has been used to conceal 
the taste of cod liver oil and of castor oil. It also 
finds some use as a perfuming agent in cosmetic 
preparations. 

Amygdalin itself is practically non-toxic, but 
when swallowed may be decomposed, by enzymes 
present in ingested foods in the alimentary canal, 
leading to the formation of hydrocyanic acid. 

Storage. — Preserve "in well-filled, tight con- 
tainers, and avoid exposure to excessive heat." 
N.F. 

PURIFIED VOLATILE OIL OF 
BITTER ALMOND. B.P. 

Oleum Amygdalae Volatile Purificatum 

This is a very different preparation from the 
N.F. Bitter Almond Oil. The B.P. oil is prepared 
from the cake of seeds of bitter almonds, peach 
kernels or apricot kernels, from which the fixed 
oil has been expressed, by distilling with water 
and subsequently removing the hydrocyanic acid. 
It should contain not less than 95.0 per cent 
w w of benzaldehyde. 

The B.P. does not mention any method for re- 
moving the hydrocyanic acid but this may be ac- 
complished by treating the oil with ferrous sulfate 
and calcium hydroxide, followed by redistillation. 

Description and Standards. — This is a 
colorless or pale yellow liquid with the character- 
istic odor and taste of bitter almonds. Its weight 
per ml., at 20°, is 1.042 to 1.046; it has a re- 
fractive index at 20° of 1.542 to 1.546. It is 
soluble in two parts of 70 per cent alcohol. The 
absence of hydrocyanic acid is shown by shaking 
the oil with sodium hydroxide solution, adding 
ferrous sulphate solution, warming and acidulating 
with dilute hydrochloric acid; no blue color 
should be produced. A test, in which an alcohol 
solution of the oil is titrated with 0.1 N alcoholic 



Part I 



Almond Oil, Expressed 45 



potassium hydroxide, limits the amount of 
benzoic acid which may be present. 

Assay. — This is essentially similar to the 
method employed for the assay of benzaldehyde 
in bitter almond oil or in the official product 
benzaldehyde. 

This oil is intended as a flavoring agent for the 
same purposes as benzaldehyde. The B.P. uses it 
as a flavor for emulsion of cod liver oil. 

EXPRESSED ALMOND OIL. 

U.S.P. (B.P.) 

Almond Oil, Sweet Almond Oil, [Oleum Amygdalae 
Expressum] 

"Expressed Almond Oil is the fixed oil obtained 
from the kernels of varieties of Prunus Amygdalus 
Batsch (Fam. Rosacea)." U.S.P. The B.P. rec- 
ognizes as the sources of this oil the seeds of 
Primus amygdalus Batsch. var. dulcis (DC.) 
Koehne, or of Prunus amygdalus Batsch. var. 
amara (DC.) Focke. 

B.P. Almond Oil; Oleum Amygdalae. Oil of Sweet Al- 
mond. Oleum Amygdalarum. Ft. Huile d'arr.ande. Ger. 
Mandeldl. It. Olio di mandorle dolci. Sp. Aceite de 
almendras; Aceite de Almendra por Expresion. 

For description of Prunus Amygdalus Batsch, 
also known as Primus communis Arcang., see 
under Bitter Almond Oil. 

In normal times we are supplied with sweet 
almonds chiefly from Spain, Italy, France, and 
southern California. They are separated into the 
soft-shelled and hard-shelled varieties, the former 
of which come from Marseilles and Bordeaux, the 
latter from Malaga. From the latter port they 
are sometimes exported without the shell. In 
British commerce, the two chief varieties are the 
Jordan and Valencia almonds, the former im- 
ported from Malaga, the latter from Valencia; 
the former are longer, narrower, more pointed, 
and more highly esteemed than the latter. Each 
kernel consists of two white cotyledons, enclosed 
in a thin, yellowish-brown, bitter skin, which is 
easily separable after immersion in boiling water. 
Deprived of this covering they are called blanched 
almonds. On exposure to the air they are apt to 
become rancid; but, if thoroughly dried and kept 
in well-closed glass vessels, they may be pre- 
served unaltered for many years. They are, when 
blanched, without odor, and have a sweet, pleas- 
ant taste, which has rendered them a favorite 
article of diet in all countries where they are 
readily attainable. 

Sweet almonds are no longer official. The B.P. 
1914 described them, under the name Amygdala 
Dulcis, as follows : 

"About two and a half centimeters or some- 
what more in length, nearly oblong in outline, 
more or less compressed, pointed at one extrem- 
ity and rounded at the other. Testa cinnamon- 
brown, thin and scaly. Seed exalbuminous, con- 
taining two large planoconvex oily cotyledons. 
Taste bland; when triturated with water forms a 
white emulsion with no marked odor." B.P. 1914. 

The U.S.P. IX gave the following description of 
microscopic appearance. "The powder is creamy- 
white, exhibiting numerous very small oil globules, 
0.001 mm. or less in diameter, and larger oil 
globules and crystalloids, the latter sometimes 



with adhering globoids; fragments of parenchyma 
of endosperm, containing oil globules and aleurone 
grains; also occasional fragments of seed-coat 
with characteristic, more or less scattered, large, 
elliptical, thin-walled, strongly lignified epidermal 
cells and narrow, closely spiral tracheae. Starch 
grains are absent." U.S.P. IX. 

Sweet almonds contain up to about 54 per cent 
of fixed oil, 24 per cent of protein, 6 per cent of 
uncrystallizable sugar, 3 per cent of gum, 9 per 
cent of fibrous matter, 3.5 per cent of water, and 
0.5 per cent of acetic acid. They yield the enzyme 
emulsion but do not contain amygdalin. "Almond 
cake," a by-product in the manufacture of almond 
oil, is largely used in the preparation of a class 
of detergent powders known as "almond meal." 
It is also used as a diabetic food and sometimes 
as an adulterant of ground spices and powdered 
drugs. Almond cake may be poisonous if it is 
made with bitter almond as it would contain 
emulsin and amygdalin and yield hydrocyanic 
acid. 

Expressed almond oil may be obtained equally 
pure from sweet and from bitter almonds. In its 
preparation, the almonds, deprived of a reddish- 
brown powder adhering to their surface by being 
rubbed together in a piece of coarse linen, are 
ground in a mill or bruised in a stone mortar, and 
then pressed in canvas sacks between slightly 
warm plates of iron. The oil, which is at first 
turbid, is clarified by filtration. Sometimes the 
almonds are steeped in hot water, deprived of 
their cuticle, and dried by heating, previous to 
expression. The oil thus obtained is free from 
color, but is in no other respect better; it is more 
likely to become rancid on keeping. Bitter almonds 
treated in this way impart an odor of hydrocyanic 
acid to the oil. The yield of oil from sweet 
almond is from 40 to 55 per cent, being slightly 
less from the bitter. Though sometimes expressed 
in this country from imported almonds, the oil is 
generally brought from Europe. During World 
War II, when the oil was not available, the 
U.S.P. permitted the use of persic oil in ointments 
in which expressed almond oil is an ingredient. 

Description. — "Expressed Almond Oil is a 
clear, pale straw-colored or colorless, oily liquid. 
It is almost odorless, and has a bland taste. It re- 
mains clear at —10°, and does not congeal until 
cooled to nearly — 20°. Expressed Almond Oil is 
slightly soluble in alcohol, but is miscible with 
ether, with chloroform, with benzene, and with 
petroleum benzin. The specific gravity of Ex- 
pressed Almond Oil is not less than 0.910 and not 
more than 0.915." U.S.P. 

Standards and Tests. — Foreign kernel oils. — 
Not more than a slight color develops on shaking 
vigorously for 5 minutes a mixture of 2 ml. of ex- 
pressed almond oil, 1 ml. of fuming nitric acid and 
1 ml. of water. Cottonseed or sesame oil. — The 
oil meets the requirements of the tests for cotton- 
seed oil and for sesame oil under Olive Oil. Min- 
eral oil and foreign fatty oils. — A clear solution 
results on adding water to the residue remaining 
after the evaporation of the alcohol from a mix- 
ture of expressed almond oil, sodium hydroxide 
solution, and alcohol which has been heated to 
saponify the oil {mineral oil). On adding an ex- 



46 Almond Oil, Expressed 



Part I 



cess of hydrochloric acid to the aqueous solution 
the fatty acids which separate, after washing with 
warm water and clarifying by heating on a water 
bath, remain clear for at least 30 minutes when 
cooled to 15° and kept at this temperature, with- 
out stirring. Foreign oils. — A clear solution re- 
sults when a portion of the fatty acids separated 
in the preceding test is mixed with an equal vol- 
ume of alcohol and cooled to 15° ; no turbidity de- 
velops on adding another volume of alcohol (olive, 
peanut, or other fixed oils). Free fatty acids. — 
Not more than 5 ml. of 0.1 N sodium hydroxide is 
required for neutralization of 10 Gm. of oil. 
Iodine value. — Not less than 95 and not more 
than 105. Saponification value. — Not less than 
190 and not more than 200. U.S.P. 

The B.P. gives the refractive index, at 40°, as 
1.4624 to 1.4650, and the acid value as not more 
than 4.0. 

Expressed almond oil consists chiefly of olein 
with traces of linolein; there is no stearin present. 
It belongs among the "non-drying" oils or "vege- 
table oleins." 

Expressed almond oil has been adulterated with 
oils from peach or apricot kernels, olive oil, lard 
oil, cottonseed oil, and peanut oil; these may be 
detected by the official tests. Many of these 
adulterants may also be detected by determining 
the absorption spectrum of the sample. Almond 
oil differs from most vegetable oils in neither 
giving a banded spectrum nor producing strong 
absorption in the red or violet. 

Uses. — Expressed almond oil possesses the 
emollient properties of the other fixed oils, over 
most of which it has the advantage of comparative 
tastelessness, freedom from odor, and lack of 
tendency to become gummy. It is widely used 
as an emollient for chapped hands and other in- 
flamed conditions of the skin. The oil is some- 
times employed in the preparation of cold creams, 
as in the official rose water ointment, and in 
similar cosmetic preparations. Occasionally it is 
used for its laxative effect. 

Dose, 4 to 30 ml. (approximately one 
fluidrachm to one fluidounce). 

Storage. — Preserve "in tight containers." 
U.S.P. 

Off. Prep.— Rose Water Ointment, US.P. 

ALOE. U.S.P. (B.P.) 

Aloes, [Aloe] 

"Aloe is the dried juice of the leaves of Aloe 
Perryi Baker, known in commerce as Socotrine 
Aloe, or of Aloe barbadensis Miller (Aloe vera 
Linne'), known in commerce as Curasao Aloe, or 
of Aloe ferox Miller and hybrids of this species 
with Aloe africana Miller and Aloe spicata Baker, 
known in commerce as Cape Aloe (Fam. Lili- 
acetz). Aloe yields not less than 50 per cent of 
water-soluble extractive." U.S.P. 

The B.P. recognizes Aloes as the residue ob- 
tained by evaporating to dryness the liquid which 
drains from leaves cut from various species of 
Aloe. Not less than 75.0 per cent of water- 
soluble extractive is required. 

B.P. Aloes. Fr. Aloes. Cer. Aloe. It. Aloe. Sp. Acibar; 
Aloe. 



The genus Aloe comprises about 170 species 
mostly native to eastern and southern Africa, but 
some have spread to the Mediterranean basin 
and have been introduced into the West Indies, 
East Indies, Europe, and the Americas. The leaves 
of the Aloe plants are fleshy and succulent. In 
cross section they exhibit a strongly cuticularized 
epidermis surrounding a mesophyll of two zones, 
viz.: an outer cortical zone composed of paren- 
chyma containing numerous chloroplastids, as- 
similation starch and occasional bundles of 
raphides of calcium oxalate, and an inner, clear 
central zone consisting of large, thin-walled 
parenchyma with an abundance of mucilage and 
scattered cells containing raphides of calcium 
oxalate. On the border of the outer cortical and 
clear central zones is to be noted an ellipse of 
vascular bundles each of which is surrounded by 
a pericycle and endodermis. The bitter juice is 
contained within the pericyclic cells and some- 
times in the parenchyma cells adjacent. 

Most plants belonging to the genus are capable 
of yielding a bitter juice which is laxative and 
there is little doubt that in many cases a com- 
mercial aloe exported from one country is the 
product of the leaves of several species. 

1. Aloe Perryi Baker. — The true Socotrine aloe 
is a perennial herb, growing abundantly upon the 
island of Socotra, especially in the limestone 
tracts, from the sea level to an altitude of 3,000 
feet and also found in eastern Africa and in 
Arabia. It has a trunk one foot high which bears 
on its summit a dense rosette of pale green or 
reddish, succulent, lanceolate leaves which are 
somewhat striate but not mottled. They are 
channeled above, convex below and show brown- 
tipped, marginal spines. From the center of the 
leaf rosette there extends a long raceme of tubu- 
lar, reddish flowers which later turn yellow. The 
fruit is a membranous capsule. 

2. Aloe barbadensis Mill. (A. vera "L."; A. 
vulgaris Lamarck). — This species, which is the 
source of Curasao aloe, has a very short, woody 
stem, and lanceolate embracing leaves, which are 
first spreading, then ascending, of a glaucous 
green color, when young, irregularly mottled with 
white spots, flat on the upper surface, convex 
beneath, and armed with hard, pale spines, dis- 
tant from each other, and perpendicular to the 
margin. It has bright yellow flowers arranged in 
a spicate inflorescence. A. barbadensis is a native 
of southeastern Europe, northern Africa, and 
Madagascar. It is cultivated in Italy, Sicily, 
Malta, and especially in the West Indies, where 
it contributes largely in the Curacao or Barbados 
aloe. 

3. Aloe ferox Miller, one of the three South 
African, tree-like species yielding Cape aloe, is 
one of the tallest species of the genus. It has a 
forked stem ten to fifteen feet long, four to six 
inches in diameter; furnished at the top with a 
dense rosette containing thirty to fifty leaves, 
which are lanceolate, one and one-half to two 
feet long, very rigid, with copious prickles on 
back and face, the purplish margin armed with 
reddish brown-tipped, deltoid or cuspidate prickles 
one-eighth to one-sixth of an inch long. Its in- 
florescence consists of a panicle of tubular, striped 



Part I 



Aloe 



47 



whitish flowers. This species readily hybridizes 
with A. africana and A. spicata and hybrids of 
these yield some of the Cape aloes of the market. 

4. Aloe africana Mill., an arborescent South 
African species, has a simple tall trunk which 
bears on its summit a few triangular-oblong, 
glaucous, green leaves with large, horny, mar- 
ginal teeth. Its flowers are tubular and yellow 
and are borne on a candelabra-like panicle. It is 
a native of the Cape Colony. 

5. Aloe spicata Baker {A. Eru var. cornuta 
Berger) is a tall, branched aloe indigenous to 
tropical southern Africa. It possesses pale, glossy, 
fleshy leaves with white blotches and a panicle 
of campanulate yellow flowers. 

For further details on species of Aloe, see 
Baker (Jour. Linnean Soc, Botany, Vol. 1880, 
pp. 148-241). 

Commercial History and Varieties. — 

Socotrine Aloe. — This variety appears to have 
been the original aloe, having been produced in 
the island of Socotra at least as early as the time 
of Alexander the Great, 333 B.C., who is said to 
have sent a commission to investigate its manu- 
facture. 

The leaves, which are cut at any time of year, 
are allowed to drain into a goat's or sheep's skin, 
and the gathered juice permitted to evaporate 
spontaneously. In the course of about one month, 
when it has become thick and viscid, it is known 
by the Arabic name of Jayef Gesheeshah ; several 
weeks subsequently when it has become hard, it is 
called Jayef Kasahul. Due to its exposure through- 
out the long process of desiccation, all the 
varieties of Socotrine aloes contain much foreign 
matter. 

Socotrine aloe is brought from the island of 
Socotra, the east coast of Africa, and from the 
Arabian coast by Arab traders to Bombay and 
exported in barrels, kegs, goats' skins, or tins 
to London, whence it is shipped to the United 
States. 

The best Socotrine aloe occurs in pieces vary- 
ing from a dark ruby-red to a yellowish or red- 
dish-brown, more or less semi-transparent, with 
a glossy surface and a smooth or ragged but not 
conchoidal fracture, and yielding a bright golden- 
yellow powder. Its odor is peculiar, almost 
fragrant, especially developed by breathing upon 
the aloe, and its bitter, disagreeable taste has a 
somewhat aromatic tang. The poorest variety of 
Socotrine aloe, Mocha aloes of the East, is soft, 
dark, and malodorous. 

Zanzibar Aloe is a hepatic variety of Socotrine 
aloe made by slow evaporation of the juice. It 
occurs in liver-brown masses, with a dull, waxy 
but nearly smooth and even fracture, a character- 
istic odor and a nauseous, bitter taste. It is poured 
into skins which are packed in cases for ship- 
ment. The variability of Socotrine aloe probably 
depends upon not only different methods of 
preparation but a different origin. 

Curacao, or West Indian, Aloe. — This aloe, 
which is produced in the Dutch West Indian 
Islands, chiefly in the islands of Aruba, Bonaire 
and Curasao, appears not to have entered com- 
merce extensively before the early part of the 
19th century, but at present constitutes a very 



large proportion of commercial aloe. It occurs 
chiefly in three forms: first, an opaque, brittle 
aloe, showing abundant crystals under the micro- 
scope, and sold in gourds usually as Barbados 
aloe; second, aloes having an appearance like the 
first variety but sold in cases; third, glossy 
Curagao or Capey Curacao aloe, which occurs in 
cases and is glossy and transparent. This variety 
may become opaque upon long storage due to the 
gradual crystallization of the aloin. Small frag- 
ments show a garnet-red color. 

Curagao aloe is collected in the Dutch West 
Indies by workers during the early spring. The 
leaves are cut off at their bases and placed cut end 
downward in V-shaped troughs which are arranged 
on an incline. The juice, in trickling from the 
leaves, runs down the sides of the trough and 
through an aperture at its lower end into a re- 
ceptacle beneath. As the receptacles are filled 
with the juice, their contents are poured into a 
cask and either evaporated spontaneously or by 
boiling in copper vessels. As soon as the juice has 
thickened to the proper consistency, it is poured 
into gourd shells or boxes and allowed to harden. 
This aloes is shipped direct to the United States 
from Aruba, Curagao and Bonaire. 

Kremel gives a method to distinguish Curagao 
aloe from other kinds by adding to it a little 
cupric sulfate solution, then some saturated solu- 
tion of common salt, which makes the color an 
intense carmine. The reaction is due to cupro- 
aloin. Curagao aloe, deprived of its aloin, has 
occurred in the markets; this fraudulent product 
was then sold as Cape aloe; the odor of the 
Curagao variety still remains. 

Cape Aloe. — This variety, while chiefly from 
Aloe ferox, is derived, at times, from hybrids of 
this species with Aloe africana and Aloe spicata. 
The general method of collecting Cape aloe is to 
allow the juice in the excised leaves to drain into 
a canvas or goat's skin, which has been so placed 
in a hole in the ground as to force the juice to 
collect in the center. Later this juice is poured 
into a drum or tin, in which it is boiled for 4 or 
5 hours with constant stirring and, when suffi- 
ciently concentrated, poured into boxes or bar- 
rels and allowed to harden. In these containers 
it is shipped from Mossel Bay and Port Eliza- 
beth to Cape Town, thence to Europe and Amer- 
ica. Cape aloe differs from Socotrine aloe, espe- 
cially in its brilliant conchoidal fracture and 
peculiar odor, which is strong, but neither nau- 
seous nor aromatic. When freshly broken it has a 
very dark olive or greenish color approaching to 
black, presents a smooth, bright, almost glassy 
surface, and if held up to the light appears trans- 
lucent at its edges. The small fragments also are 
semi-transparent, and have a tinge of yellow or 
red mixed with the deep olive of the opaque mass. 
Cape aloe, when quite hard, is very brittle and 
readily powdered; but in very hot weather it is 
apt to become somewhat soft and tenacious, and 
the interior of the pieces is occasionally more or 
less so even in winter. 

Uganda, or crown, aloe is a brand of Cape aloe 
formerly produced by manufacturers who bought 
the aloe juice from the collectors, allowed it to 
undergo a slight fermentation, and dried it in the 



48 



Aloe 



Part I 



sun in wooden troughs. It was sent into com- 
merce in bags containing coarse or fine powder, 
or chips, and in bricks wrapped in red paper; it 
has a very bitter, aromatic taste and a strongly 
aromatic odor. The bricks were of a hepatic 
brown color, with a resinous fracture, which had 
a bronzy-gold luster by refracted light. Uganda 
aloe is now practically obsolete. 

An adulterant in powdered Cape aloe is a 
ferruginous clay associated with calcium carbon- 
ate. The method of detecting this adulterant is 
based on the fact that pure Cape aloe dissolves in 
ammonium hydroxide solution diluted with nine 
times its volume of distilled water. The adulterant 
can be readily separated, and the amount esti- 
mated by its insolubility, Leger (/. phartn. chim., 
1934, 19, 533). 

Other Varieties. — Besides the above certain 
other forms of aloe have appeared from time to 
time in commerce. Barbados aloe, which is the 
hepatic sub-variety of Curagao aloe, appears to 
have been brought to London as early as 1693. 
Small quantities still appear occasionally on the 
American markets. Barbados aloe is produced 
from A. barbadensis. 

Barbados aloe which is erroneously recognized 
by the B.P. as the same as Curasao aloes, varies 
in color from very dark blackish-brown through 
reddish-brown and liver-colored to orange-brown. 
It yields a dull olive-yellow powder, of a dis- 
agreeable, even nauseous odor, and it was de- 
scribed in the British Pharmacopoeia as follows: 
"Fracture either dull and waxy, in which case 
small splinters are opaque; or smooth and glassy, 
in which case the splinters are transparent; the 
opaque variety examined under the microscope 
exhibits numerous minute crystals embedded in 
a transparent mass." B.P., 1898. "Mixed with 
nitric acid, it acquires a red color. Barbados Aloes 
is not colored, or acquires only a light bluish- 
green tint, on being mixed with sulphuric acid 
and blowing the vapor of nitric acid over the 
mixture (difference from Natal aloe)." U.S.P., 
1890. 

Natal aloe is a variety coming from Natal on 
the southeast coast of Africa, the origin of which 
is not definitely ascertained but is possibly A. 
candelabrum Berger. It occurs in irregular, usually 
opaque pieces, with a fracture much less shining 
than that of Cape aloe and a totally different 
color, having a greenish slate hue. It yields a 
grayish-green or pale yellow powder, which has 
the odor of Cape aloe. It is less soluble than 
Cape aloe. 

When powdered Natal aloe is mixed with a 
little sulfuric acid and the fumes of nitric acid 
are blown over it, a deep blue coloration is 
produced. 

Hepatic aloe, as well as fetid, caballine or horse 
aloe, have no proper claim to be considered dis- 
tinct varieties, being simply inferior aloe of 
various origins, the first liver-colored, the second 
blackish and fetid and full of impurities. 

Jafferabad aloe, supposed to be the same as 
Mocha aloe, has been shown to be the product of 
A. abyssinica Lam., and is said by Shenstone to 
contain ^-barbaloin. (Am. J. Pharm., 1883, 92.) 
Aloe made in India from the A. barbadensis is 



known as Musambra aloe. It appears to be a 
very inferior variety, and rarely, if ever, reaches 
Europe. 

The labels under which aloe is sold often have 
little or no connection with the place of produc- 
tion, or with the variety of aloes in the package. 
This fact has probably come about through the 
indifference of users to the variety of the aloe 
which they are purchasing, an indifference largely 
due to the common habit of buying aloe in 
powder. 

Wilbert (Am. J. Pharm., 1903) proposed that 
aloe should be classified as follows: Aloe A. — Con- 
taining barbaloin; responds to Borntrager's test 
for emodin, but does not give a distinct red color 
with nitric acid, or with Klunge's test. Aloe B. — 
Containing isobarbaloin with barbaloin; responds 
to Borntrager's test for emodin, and also has a 
deep red color with strong nitric acid, or with 
Klunge's test. 

Fairbairn (Pharm. J., 1946, 102, 381) has de- 
scribed the microscopy of the common commercial 
varieties of aloe. 

In 1952 importations of aloe into the United 
States amounted to 413,847 pounds, most of it 
from the Union of South Africa and N. Antilles, 
although considerable came also from the Do- 
minican Republic and Venezuela. 

Description. — "Unground Socotrine Aloe 
occurs in reddish black to brownish black, 
opaque, smooth, glistening masses. Its fractured 
surface is somewhat conchoidal. It has a char- 
acteristic odor. 

"Unground Curagao Aloe occurs in brownish 
black, opaque masses. Its fractured surface is 
uneven, waxy, and somewhat resinous. It has a 
characteristic, disagreeable odor. 

"Unground Cape Aloe occurs in dusky to dark 
brown irregular masses, the surfaces of which are 
often covered with a yellowish powder. Its frac- 
ture is smooth and glassy. Its odor is character- 
istic, somewhat sour and disagreeable. 

The taste of each variety of Aloe is nauseous 
and very bitter. 

"Powdered Aloe is yellow, yellowish brown to 
olive brown in color. When mounted in a bland 
expressed oil it appears as greenish yellow to red- 
dish brown angular or irregular fragments, the 
hues of which depend to some extent upon the 
thickness of the fragments." U.S.P. 

Standards and Tests. — Identification. — (1) 
Powdered aloe dissolves in nitric acid with effer- 
vescence; the solution is reddish brown to brown 
or green. (2) The aqueous extract prepared by 
shaking 1 Gm. of finely powdered aloe with 25 
ml. of cold water during 2 hours, filtering, then 
washing the filter and residue with cold water to 
yield 100 ml. of filtrate exhibits the following 
colors when viewed in the bulb of a 100 ml. volu- 
metric flask: dark yellow with Socotrine aloe, 
dark orange with Curagao aloe, and greenish yel- 
low with Cape aloe. The filtrate darkens on stand- 
ing. (3) Addition of 2 ml. of nitric acid to 5 ml. 
of the filtrate from test (2) produces the follow- 
ing colors: yellow with Socotrine aloe, reddish 
orange with Curagao aloe, and a reddish brown 
changing rapidly to green with Cape aloe. (4) 
Addition of 45 ml. of water and 20 ml. of a 1 in 



Part I 



Aloe 



49 



20 solution of sodium borate to 5 ml. of the 
filtrate from test (2) produces a greenish yellow 
or yellowish green fluorescence which on standing 
turns to a moderate yellowish orange to brown 
color. Water. — Not over 12 per cent, when dried 
at 105° for 5 hours. Ash. — Not over 4 per cent. 
Alcohol-insoluble matter. — Not over 10 per cent, 
when 1 Gm. of powdered aloe is extracted with 
50 ml. of boiling alcohol, the residue being dried 
to constant weight at 105°. U.S. P. 

Rosenthaler (Pharm. Acta. Helv., 1937, 12, 
96) proposed two tests for aloe: (1) An aqueous 
solution of aloe is heated with sodium hydroxide 
and ammonium sulfide; Cape aloe or Barbados 
aloe turns green or greenish brown, Natal aloe 
brown. The reaction is given by both aloin and 
barbaloin. (2) A solution of aloe is heated with 
sodium hydroxide and an ammonium salt: Bar- 
bados aloe gives a purple color, Natal a bluish- 
purple, Cape aloe does not react. The reaction is 
a test for isobarbaloin. 

Keenan and Welsh (/. A. Ph. A., 1942, 31, 535) 
reported that a 5 per cent solution of gold chloride 
gave superior results to the other commonly used 
microchemical agents with barbaloin and isobar- 
baloin, and suggest its use in distinguishing dif- 
ferent varieties of aloe. With Curasao aloe it gave 
an immediate red color, with Cape aloe a green, 
while Socotrine aloe remained brown. For other 
tests for distinguishing varieties of aloes see 
Allen's Commercial Organic Analysis, Volume 8, 
Fifth Edition (1930). 

Assay.— Determine the per cent of water-sol- 
uble extractive. U.S.P. The B.P. requires not less 
than 75.0 per cent of water-soluble extractive, 
calculated with reference to the air-dried drug. 

Various methods of assaying aloe, utilizing a 
determination of the content of aloin, have been 
proposed. Goldner (/. A. Ph. A., 1932, 21, 658) 
concluded that none of the seven methods he in- 
vestigated was satisfactory. Eaton (J.A.O.A.C., 
1932, 15, 407) devised a method in which the 
aloin is acetylized to aloin hexa-acetate and 
weighed in this form; the method is officially 
recognized in the A.O.A.C. Methods of Analysis. 
Valaer and Mallory (Am. J. Pharm., 1934, 106, 
81) proposed that aloe and its preparations be 
assayed by determining the free emodin and the 
total emodin content; their method is based on a 
measurement of the depth of color produced by 
emodin in a strongly alkalinized solution. 

Constituents. — The chemistry of aloe is in- 
completely known. It is generally believed that 
aloe owes its purgative properties to the presence 
of one or more of three pentosides known as bar- 
baloin (aloin), isobarbaloin and beta-barbaloin. 
For lack of satisfactory assay methods the con- 
tent of these constituents is not known with any 
degree of certainty (see under Aloin). Viehoever 
(Am. J. Pharm., 1935, 107, 47) considers the 
resin fraction of aloe to be of equal importance, 
a view previously expressed by Kiefer (Pharm. 
Ztg., 1925, 70, 1775). Chopra and Ghosh (Arch. 
Pharm., 1938, 276, 348) reported that A. vera 
var. officinalis (A. indica) contains no aloin. 

Of the three pentosides, barbaloin (which is 
probably identical with the substances previously 
described as socaloin and capaloin) is the most 



important. It crystallizes in the form of pale 
yellow needles. Isobarbaloin is isomeric with bar- 
baloin; the former remains in the mother liquor 
when barbaloin is crystallized from methanol 
solution; the two compounds also give different 
color reactions (see above). Beta-barbaloin is a 
non-crystallizable optical isomer of barbaloin. 
Hydrolysis of barbaloin in acid solution gives a 
complex mixture in which aloe-emodin (1,8- 
dihydroxy-3-(hydroxymethyl)anthraquinone) and 
D-arabinose have been identified. Leger (Bull. soc. 
chim., 1936 [5], 3, 435) believes barbaloin is an 
ether formed by the condensation of D-arabinose 
with aloe-emodin, but objections to this formula- 
tion have been raised by Rosenthaler (Pharm. 
Acta. Helv., 1934, 9, 9) and by Foster and Gard- 
ner (J.A.C.S., 1936, 58, 597). For data on the 
hydrolysis of the aloins see Gardner and Camp- 
bell (J.A.C.S., 1942, 64, 1378). Brody et al. 
(J. A. Ph. A., 1950, 39, 666) isolated from 
Curacao aloe, by chromatographic methods, aloe- 
emodin, isoemodin (3,5,8-trihydroxy-2-methyl- 
anthraquinone), and anthranols, which are re- 
ported to exist both in the free state and in 
glycosidal combination. 

Uses. — Aloe was known to the ancients, being 
cultivated in the island of Socotra as far back 
as the time of Alexander the Great, and is men- 
tioned in the works of Dioscorides and of Celsus. 
It has been employed for eczematous skin condi- 
tions in China, India and Tibet under the names 
lu hid, musabbar and jelly leeks respectively (Cole 
and Chen, Arch. Dermat. Syph., 1943, 47, 250). 
Its cathartic action is due to a stimulation of 
peristalsis, especially in the larger bowel, prob- 
ably the result of a local irritant effect upon the 
mucous membrane, although there is some evi- 
dence that it exercises a specific stimulant effect 
upon unstriped muscles; considerable griping pain 
is often associated with its action. It is more irri- 
tating than cascara sagrada, senna and rhubarb. 
As its action is largely limited to the colon it is 
not to be recommended in those conditions in 
which it is desirable to clean out the whole ali- 
mentary canal, and as its effect is largely the result 
of local irritation it should be avoided in inflam- 
matory conditions of the intestine. It does not 
act until 8 to 12 hours after ingestion. In chronic 
constipation, especially when dependent upon an 
atonic condition of the lower bowel, it is very 
useful. The presence of bile in the bowel seems 
to be essential for the most effective action of 
this drug, and when this secretion is lacking it is 
advisable to administer some preparation of bile 
in conjunction with the aloes. Soap also appears 
to enhance the cathartic action of this drug. Ivy 
and his associates (Quart. Bull. Northwest. U. 
Med. Sch., 1945, 19, 102) reported that thera- 
peutic doses of aloe produce no increase in the 
bile content of the intestine. Aloe was formerly 
used in the treatment of amenorrhea. It is, how- 
ever, extremely doubtful whether it exercises any 
action on the pelvic organs other than congestion 
of the pelvic blood vessels. 

In the 16th and 17th centuries aloe was used 
locally in the treatment of wounds and burns 
but its use for this purpose entirely disappeared 
except as an ingredient in compound benzoin 



50 



Aloe 



Part I 



tincture. Collins and Collins (Am. J. Roentgen., 
1935, 33, 396) reported beneficial effects from the 
local application of freshly split leaves of the 
Aloe vera in the treatment of x-ray burns. After 
an hour of contact the darkened gummy, gelati- 
nous material was washed away with water. (See 
also Lovemna. Arch. Dermat. Syph., 1937, 36, 
838.) Crewe (Minn. Med., 1937, 20, 10) extended 
this local use of aloe leaf to the treatment of 
dermatitis and various ulcerated conditions of 
the skin. Rowe and colleagues (/. A. Ph. A., 1941, 
30, 266), in an experimental study of aloe leaf 
in x-ray burns, found that the curative principle 
occurs in both the pulp and rind of the leaf, but 
was not present in all commercial leaves nor in 
the official aloe. Cutaneous leishmaniasis was 
benefited by injections of an extract of aloe 
leaves (Filatov, Am. Rev. Soviet Med., 1945. 2, 
484). E 

Dose. — Aloe is today infrequently adminis- 
tered; its usual dose is 250 mg. (approximately 
4 grains), with a fange of 120 to 250 mg. 

Aloe Tincture, prepared by macerating 10 
per cent w/v of aloe and 20 per cent w/v of 
glycyrrhiza with diluted alcohol, was official in 
N.F.IX. Aloe Pills, made by massing a mixture 
of equal parts of aloe and hard soap with water, 
were also official in N.F.IX. 

Off. Prep. — Compound Benzoin Tincture, 
U.S.P., B.P.; Compound Colocynth Extract, N.F. 

ALOIN. X.F., B.P. 

[Aloinum] 

"Aloin is a mixture of active principles ob- 
tained irom aloe. It varies in chemical compo- 
sition and in physical and chemical properties 
according to the variety of aloe from which it 
is obtained." N.F. The B.P. defines it as a mix- 
ture of crystalline principles obtained from aloes. 

Sp. Aloina. 

Aloin, which consists principally of barbaloin 
and isobarbaloin (see under Aloe), has been pre- 
pared by many processes. That recommended 
by Tilden is as follows: 1 part of aloe is dis- 
solved in 10 parts of boiling water acidulated 
with hydrochloric acid, and allowed to cool. The 
liquid is then decanted from resinous matter, 
evaporated to about 2 parts, and set aside two 
weeks for crystals to form; the liquid portion is 
poured off, the crystals pressed, and the adherent 
resinous matter separated by shaking with etnyl 
acetate, which dissolves the resin. This process 
serves fairly well for obtaining aloin from Bar- 
bados or Curagao aloe. Aloin from Socotrine aloe 
is best obtained by digesting it in 3 parts of 
alcohol for 24 hours, then transferring to a water 
bath, and boiling for 2 hours. After cooling, the 
liquid is filtered and set aside to crystallize. The 
crystals are washed with alcohol and dried. The 
yield is about 10 per cent. Schafer (Pharm. J., 
1897, p. 287) obtained from 15 to 30 per cent of 
crystallized aloin from commercial aloe by the 
following process: 50 Gm. of aloe dissolved in 
300 ml. of hot water is slightly acidulated with 
hydrochloric acid. The solution, after standing 
(for the resins to separate), is decanted, mixed 



with 50 ml. of 20 per cent ammonia water, fol- 
lowed by a solution of 15 Gm. of calcium chloride 
in 30 ml. of water. The liquid is agitated and the 
aloin-calcium compound which separates is col- 
lected, drained, and mixed in a mortar with a 
slight excess of hydrochloric acid; the mixture of 
aloin and calcium chloride is dissolved in the 
smallest possible quantity of boiling water, fil- 
tered, and the filtrate cooled by means of ice; 
the aloin crystallizes. This method was recom- 
mended by Snyder as a procedure for evaluating 
aloe (see Viehoever, Am. J. Pharm., 1935, 107, 
58) and was found by Smith, Jordan and De Kay 
(/. A. Ph. A., 1944, 33, 57; to be best adapted 
for extracting aloin in the assay of Barbados and 
Curasao aloe. For chemistry of aloin, see under 
Aloe. 

Description. — "Aloin occurs as a lemon yel- 
low to dark yellow, microcrystalline powder, or 
as minute crystals. It is odorless, or has a slight 
odor of aloe. Its taste is intensely bitter. Aloin 
darkens on exposure to fight and air. A saturated 
solution of Aloin is yellow but becomes brown 
on standing. Its solutions are neutral or acid to 
litmus paper. Aloin is soluble in water, in alcohol, 
and in acetone, the degree of solubility varying 
with its composition. It is slightly soluble in 
ether." N.F. 

Standards and Tests. — Identification. — (1) 
Aloin dissolves in ammonia T.S. and in alkali 
hydroxide solutions with formation of a red color 
(or yellow turning to red) and a green fluores- 
cence. (2) A brownish green color results when 
a drop of ferric chloride T.S. is added to an 
alcohol solution of aloin. Residue on ignition. — 
Not over 0.6 per cent. Water-insoluble sub- 
stances. — Not over 1.5 per cent of residue is ob- 
tained when 1 Gm. of aloin is agitated during 
2 hours with 120 ml. of water, at 25°, the insoluble 
matter being collected on a filter paper or in a 
filtering crucible, washed with 25 ml. of water, 
and dried at 105° for 1 hour prior to weighing. 
Emodin. — Xot more than a faint, pink color 
results when the filtrate from a 1 in 10 benzene 
extract of aloin is shaken with an equal volume 
of a 5 per cent solution of ammonia. N.F. 

Aloin of commerce has been frequently con- 
taminated with large amounts of resin, indicat- 
ing lack of care in manufacturing. The N.F. test 
for water-insoluble substances limits the amount 
of such contamination to 1.5 per cent. Smith 
et al. (J. A. Ph. A., 1944, 33, 59) called atten- 
tion to the fact that aloins from different species 
of aloe give different reactions in the various 
color tests. 

Uses. — Because of the absence of resin the 
cathartic action of aloin is relatively milder than 
that of aloe. Although it is capable of producing 
purgative effects, it is never used practically in 
this manner. Aloin has enjoyed wide use in 
chronic constipation. It is often combined with 
belladonna to overcome the tendency to griping. 
However, the action of belladonna is rapid and 
brief compared with that of aloin. Aloin may pro- 
duce renal irritation and color the urine red if 
the latter is alkaline. S 

Dose, 10 to 60 mg. (approximately % to 1 
grain). 



Part I 



Alum 



51 



Storage. — Preserve "in tight, light-resistant 
containers." N.F. 

Off. Prep. — Aloin, Belladonna, Cascara and 
Podophyllum Pills. N.F. 

ALOIN, BELLADONNA, CASCARA 
AND PODOPHYLLUM PILLS. N.F. 

Hinkle's Pills, [Pilulae Aloini, Belladonna, 
Cascarae et Podophylli] 

Prepare 100 pills, according to the General 
Directions (see under Pills), from 1.6 Gm. of 
cascara sagrada extract, 1.6 Gm. of aloin, 1 Gm. 
of podophyllum resin, 0.8 Gm. of belladonna ex- 
tract, 0.4 Gm. of ginger oleoresin, and 1 Gm. of 
glycyrrhiza, in fine powder, using liquid glucose 
as the excipient. N.F. 

Dose, as a laxative, one or two pills. 

ALTHEA. N.F. 

Marshmallow Root, [Althaea] 

"Althea is the dried root of Althcea officinalis 
Linne (Fam. Malvaceae), deprived of the brown, 
corky layer and small roots." N.F. 

White Mallow. Radix Bismalvae; Radix Hibisci. Fr. 
Guimauve ; Racine de guimauve. Ger. Eibischwurzel ; Bis- 
malvawurzel; Altheewurzel; Heilwurzel. It. Altea; Mal- 
vischio; Malvaccioni. Sp. Raiz de altea; Altea. 

Althcea officinalis is a perennial herb with a 
perpendicular branching root and erect woolly 
stems, from two to four feet or more in height, 
branched and leafy toward the summit. The 
plant is native to Europe, inhabiting salt marshes, 
the banks of rivers, and other moist places. It is 
found also in this country, from New England to 
New York and westward to Michigan and Arkan- 
sas. It is largely cultivated in Europe for medici- 
nal use. 

The roots should be collected in autumn from 
plants at least two years old. They are usually 
prepared for the market by removing the rootlets, 
scraping the roots free of cork and drying either 
entire or after slicing the thicker roots. 

Description. — "Unground Althea. — When en- 
tire, Althea occurs as slenderly tapering roots, up 
to 30 cm. in length and 2 cm. in diameter; exter- 
nally pale yellow to pale brown, longitudinally 
furrowed, frequently spirally twisted and covered 
with somewhat loosened bast fibers. The fracture 
of the bark is fibrous, and of the wood, short and 
granular. Internally it is yellowish; the bark is 
1 to 2 mm. thick, porous, with mucilage cells and 
is separated from the slightly radiating wood by 
a distinct darker cambium zone. Althea is fre- 
quently cut into small pieces about 5 mm. in 
thickness. Sometimes the root is found split or 
in slices. Althea has a slight odor and a sweetish, 
mucilaginous taste." N.F. For histology see N.F. X. 

"Powdered Althea is white to weak yellow. It 
consists of numerous starch grains up to 30 n in 
diameter, usually with a long central cleft; groups 
of fibers with thick, more or less lignified walls; 
vessels with scalariform thickenings or with bor- 
dered pits, and a few calcium oxalate crystals in 
rosette aggregates, from 20 to 35 (x in diameter." 
N.F. 

Standards and Tests.— Identification.— The 
mucilage obtained by stirring a mixture of 1 Gm. 



of comminuted althea with 10 ml. of cold distilled 
water during 30 minutes, then filtering through 
cotton, has a weak yellow color and is only 
slightly acid to litmus; on addition of sodium 
hydroxide T.S. it assumes a moderate to strong 
yellow color, and has neither a sour nor an am- 
moniacal odor. Foreign organic matter. — Not over 
1 per cent. Acid-insoluble ash. — Not over 1 per 
cent. N.F. 

Constituents. — Althea contains on the aver- 
age 37 per cent of starch, 35 per cent of gum, 11 
per cent of pectin, 11 per cent of sugar, 1.25 per 
cent of fat and up to 2 per cent of asparagin. 

The principle, discovered in the root by Bacon, 
by him called althein, has been found to be 
asparagin. This substance belongs to the group 
of amides and hence has been called asparamide, 
also aspargine and agedoite. It is a-aminosuccin- 
amic acid, NH 2 COCH2.CH(NH 2 )COOH. When 
treated with a strong acid it yields aminosuccinic 
(aspartic) acid which is also a product of pancre- 
atic digestion of certain proteins. Asparagin is 
found in many other plants but is of no medicinal 
importance. 

Under the title of Althcece. Folia (Marsh Mal- 
low Leaves), the N.F. V recognized the dried 
leaves of the Althcea officinalis collected in June 
or July, while the plant is in flower, and dried. 
They, like the root, have been used for their muci- 
lage, which is, however, less abundant in the 
leaves. For a description of the leaves, see U.S.D., 
22nd ed., p. 108. 

The N.F. IX recognized Althea Syrup, which 
has been used as a demulcent vehicle. It was pre- 
pared as follows : Wash 50 Gm. of althea, cut into 
small pieces, with cold distilled water. Macerate 
this with a mixture of 400 ml. of distilled water 
and 30 ml. of alcohol for 3 hours at room tempera- 
ture, without stirring; strain the mixture without 
expressing the residue, dissolve in the strained 
liquid, by agitation and without heat, 700 Gm. of 
sucrose. Add 100 ml. of glycerin and enough water 
to make 1000 ml. 

Uses. — The virtues of marshmallow are exclu- 
sively those of a demulcent. The decoction of the 
root has been much used in Europe in irritation 
and inflammation of the mucous membranes. The 
roots themselves, as well as the leaves and flowers, 
boiled and bruised, have been employed as a 
poultice. Althea also finds use as an excipient for 
pills. 

Off. Prep.— Ferrous Carbonate Pills, N.F. 

ALUM. N.F., B.F. 

Ammonium Alum, Potassium Alum, [Alumen] 

"Alum contains not less than 99.5 per cent of 
AlNH4(S0 4 )2.12HoO or of A1K(S04) 2 .12H 2 0. 
The label of the container must indicate whether 
the salt is Ammonium Alum or Potassium Alum." 
N.F. The B.P. definition is essentially the same 
and the purity rubric is identical with that of 
the N.F. 

Purified Alum. Alumen Purificatum. Sp. Alumbre. 

The term alum is a generic name for a group 
of double salts of the general formula: 
R2S04.R , 2(S04) 3 .24H 2 0, or RR'(S04) 2 .12H 2 



52 



Alum 



Part 1 



in which R is univalent and may be Na, K, Rb, 
Cs, etc., or a radical such as NH4, and R' is 
trivalent and may be Fe, Cr, Al, etc. Alums 
have been prepared in which SeOi, or TeCh, have 
replaced SO-t. 

The alum officially recognized may be either 
the double sulfate of aluminum and potassium, or 
of aluminum and ammonium. These are distin- 
guished as potassium alum and ammonium alum, 
respectively. From time to time one or the other 
of these has been given official preference, but 
at present both are recognized under the common 
title of Alum in the official compendia of the 
United States and of Great Britain. 

Potassium Alum. Potassium Aluminum Sul- 
fate. Aluminii et Potassii Sulfas; Fr. Alun de 
potassium; Alun; Sulfate double d'alumina et 
de potasse. Ger. Alaun; Kaliumalaun. It. Allume 
di potassa; Allume; Allume di rocca. Sp. Sulfato 
de aluminio y de potasio ; Alumbre. — Alum has 
been manufactured for centuries, the chemical 
having been used in the time of Pliny as a mor- 
dant for the production of bright colors. It may 
be obtained from several natural sources, among 
which the more important are the minerals alu- 
nite, bauxite and cryolite. 

Al unite (or alum stone), a mixture of alumi- 
num sulfate and potassium sulfate, is subjected 
to a roasting process, by which is formed alum 
and insoluble alumina. Upon treatment with sul- 
furic acid, the alumina passes into solution as 
aluminum sulfate; this may be recovered from 
the mother liquors after crystallization of the 
alum, or potassium sulfate may be added in suf- 
ficient quantity to convert the aluminum sulfate 
to alum. . 

Bauxite, a hydrated oxide of aluminum con- 
taining from 30 to 76 per cent of aluminum oxide, 
has become an important source of alum. Alumi- 
num sulfate obtained from this mineral is treated, 
in solution, with potassium sulfate and the alum 
obtained by crystallization. Cryolite, a double 
fluoride of sodium and aluminum, also serves as 
a source of aluminum salts, from which can be 
made also the alums. Various earths and clays, 
known as aluminous schist, alum slate, and alum 
shale furnish other sources of alum. 

Potassium alum usually crystallizes in octahe- 
dral crystals having a specific gravity of 1.75. 
When heated to 92.5°, it forms a solution in its 
water of crystallization; continued heating vola- 
tilizes the water, leaving behind a white, opaque, 
porous mass which is the official exsiccated alum 
(see Exsiccated Alum). Exposed to high heat, it is 
converted to a mixture of aluminum oxide and 
potassium sulfate. 

Ammonium Alum. Ammonium Aluminum 
Sulfate. Alumen Ammoniatum; Aluminii et 
Ammonii Sulfas; Fr. Alun d 'ammonium. Ger. 
Ammonium-alaun ; Ammoniak alaun. It. Allume 
di ammonio. Sp. Sulfato de aluminio y de amonio. 
— The preparation of ammonium alum is analo- 
gous to that of potassium alum. A solution of alu- 
minum sulfate, prepared by any of the several 
methods previously described, is treated with an 
equivalent amount of ammonium sulfate. Upon 
concentration, crystals of ammonium alum sepa- 



rate, and these may be purified by recrystalliza- 
tion. In crystalline structure and general physical 
appearance it resembles closely potassium alum. 
and it is necessary to apply chemical tests to 
differentiate the two. 

Ammonium alum forms crystals similar to 
those of potassium alum, and having a specific 
gravity of 1.63. When heated, ammonium alum 
swells up and forms a porous mass, as water and 
sulfuric acid are evolved; continued ignition at 
high temperature leaves a residue of aluminum 
oxide. 

Description. — "Alum occurs as large, color- 
less crystals, crystalline fragments, or as a white 
powder. Alum is odorless, and has a sweetish, 
strongly astringent taste. Its solutions are acid to 
litmus paper. One Gm. of Ammonium Alum dis- 
solves in 7 ml. of water, and in about 0.3 ml. of 
boiling water. One Gm. of Potassium Alum dis- 
solves in 7.5 ml. of water, and in about 0.3 ml. of 
boiling water. Alum is insoluble in alcohol. It 
is freely but slowly soluble in glycerin." N.F. 

Standards and Tests. — Identification. — (1) 
Ammonia is evolved and a precipitate, soluble in 
an excess of reagent, formed when sodium hydrox- 
ide T.S. is added to a 1 in 20 solution of am- 
monium alum. (2) When potassium alum is simi- 
larly tested no ammonia is evolved. (3) A violet 
color is imparted by potassium alum to a non- 
luminous flame. (4) A white, crystalline precipi- 
tate forms within 30 minutes on adding 10 ml. of 
sodium bitartrate T.S. to 5 ml. of a saturated 
solution of potassium alum. (S) A 1 in 20 solu- 
tion of alum responds to tests for aluminum and 
for sulfate. Alkalies and alkaline earths.— 'Sot 
over 5 mg. of residue is obtained on evaporating 
the filtrate from 1 Gm. of alum dissolved in 
100 ml. of water and precipitated with ammonia. 
Arsenic. — A solution of alum meets the require- 
ments of the test for arsenic. Heavy metals. — The 
limit is 20 parts per million. Iron — Xo blue color 
is produced immediately on adding 5 drops of 
potassium ferrocyanide T.S. to 20 ml. of a 1 in 
150 solution of alum. N.F. 

The B.P. states that when heated alum melts 
and at about 200° loses its water of crystalliza- 
tion. The presence of ammonium salts in potash 
alum is detected with alkaline potassium mercui- 
iodide; the arsenic limit for both alums is 4 parts 
per million. Otherwise the tests are similar to 
those of the N.F. 

Assay. — A sample of about 1 Gm. of alum is 
dissolved in distilled water, ammonium chloride 
is added, and the aluminum is precipitated as hy- 
drous oxide (hydroxide) by the addition of a 
slight excess of ammonia. The precipitate is fil- 
tered off, washed, dried and ignited to AI2O3; 
the weight is multiplied bv 8.894 to obtain the 
weight of A1NH4(S04)2.12H 2 0. or by 9.307 to 
obtain the weight of A1K(S04)2.12H 2 0. To 
guard against the possibility of adding enough 
ammonia to redissolve a portion of the hydrous 
aluminum oxide precipitate, the otherwise similar 
B.P. assay employs methyl red as an indicator to 
limit the concentration of ammonia. 

Incompatibilities. — Alum has the character- 
istic incompatibilities of aluminum salts and of 



Part I 



Alum, Exsiccated 



53 



the sulfates. In alkaline solution, unless the con- 
centration of hydroxyl ion is sufficiently high to 
form soluble metaluminate ion, aluminum hy- 
droxide is precipitated. Fixed alkalies liberate 
ammonia from the ammonium alum. 

Uses. — Alum is absorbed from the intestinal 
tract only in relatively small quantities, although 
Gies (J. A.M. A., 1911, 57, 57) has shown that the 
former view that it was completely excreted, un- 
absorbed, with the feces is incorrect. The anti- 
septic power of alum is lower than that of most 
salts of aluminum; according to Miquel it will 
inhibit the multiplication of bacteria in the pro- 
portion of about one part in two hundred. 

Alum is a powerful astringent with very de- 
cided irritant qualities, and when taken inter- 
nally in sufficient quantities is emetic and pur- 
gative, and may even cause gastrointestinal in- 
flammation. It is rarely used as an internal 
astringent. It has been occasionally employed 
internally in the treatment of lead colic, as a 
chemical precipitant of lead in the intestinal tract; 
it was thought also to have some beneficial action 
upon the intestines directly. It is occasionally em- 
ployed as an emetic to empty the stomach in cases 
of poisoning, but is inferior for this purpose to 
zinc sulfate. It was formerly extensively used as a 
gargle, but it exercises a destructive influence 
upon the teeth and is inferior to aluminum acetate. 

The most important use of alum today is as a 
local astringent to check excessive local sweating 
or to harden the skin, especially of the feet. Po- 
tassium alum in 10 per cent aqueous solution is 
efficient in removing flora from normal skin, but 
less so than alcohol or 0.5 per cent hydrochloric 
acid according to Myer and Vicher (Arch. Surg., 
1943, 47, 468). Such a solution hardens the skin, 
imprisoning bacteria which may be released as the 
skin softens when covered by rubber gloves. It is 
also employed as an astringent in leukorrhea. un- 
healthy ulcers, and similar conditions. As an 
astringent it is usually employed in strengths 
ranging from 1 to 5 per cent, according to the 
location to which it is applied. Occasionally pow- 
dered alum may be thinly dusted over the area. 
As a styptic it is employed as an alum stick or as 
the powdered chemical and applied directly to 
the bleeding point if easily accessible. In epistaxis 
the nares may be plugged with pledgets of cotton 
soaked in a saturated solution. When used as an 
astringent on the more delicate mucous mem- 
branes, as in conjunctivitis, it is desirable to 
modify its action by combining it with albuminous 
matter as in the form of the alum curd. This is 
made by boiling 8 Gm. of alum in 480 ml. of 
milk and straining off the whey. Concentrations 
with effective spermicidal action (0.5 to 1 per 
cent) are uncomfortably astringent, [vj 

Toxicology. — When taken in large dose, 
alum acts as an irritant poison causing burning 
in the mouth and throat followed by vomiting, 
purging, collapse, and other symptoms of toxic 
gastroenteritis. Several fatalities have been re- 
ported. The treatment of alum poisoning consists 
in the use of demulcent drinks, such as milk, 
combined with an antacid as magnesia, and com- 
bating the collapse with customary stimulants. 



For consideration of the physiological question 
of the effects of repeated small doses of alum, see 
under Aluminum. 

Dose, as an astringent, 300 mg. to 1 Gm. (ap- 
proximately 5 to 15 grains); as an emetic, 4 Gm. 
(approximately 1 drachm), dissolved in water. 

Storage. — Preserve "in well-closed contain- 
ers." N.F. 

Off. Prep.— Exsiccated Alum, N.F. 

EXSICCATED ALUM. N.F. 

Dried Alum, Burnt Alum, Exsiccated Ammonium Alum, 
Exsiccated Potassium Alum, [Alumen Exsiccatum] 

"Exsiccated Alum, dried at 200° for 4 hours, 
contains not less than 96.5 per cent of AINH4- 
(S04) 2 or of A1K(S0 4 )2. The label of the 
container must indicate whether the salt is Exsic- 
cated Ammonium Alum or Exsiccated Potassium 
Alum." N.F. 

Alumen Ustum. Fr. Alun desseche. Ger. Gebrannter 
Alaun. It. Allume usto; allume calcinato. Sp. Sulfato 
de aluminio y de potasio anhidro; Alumbre Desecado; 
Alumbre calcinado. 

Exsiccated alum may be prepared by heating 
alum, at a temperature of about 200°, until the 
water of crystallization has been volatilized. 

Description. — "Exsiccated Alum is a white, 
odorless powder. It has a sweetish, astringent 
taste, and absorbs moisture on exposure to air. 
One Gm. of Exsiccated Alum dissolves very 
slowly and usually incompletely in about 20 ml. of 
water. One Gm. of it dissolves in about 2 ml. of 
boiling water. It is insoluble in alcohol." N.F. 

Standards and Tests. — Identification. — Ex- 
siccated alum responds to the identification tests 
under alum. Loss on drying. — Not over 10 per 
cent, on drying at 200° for 4 hours. Water- 
insoluble substances. — Not more than 50 mg. of 
residue is obtained from 2 Gm. of exsiccated 
alum added to 40 ml. of water and occasionally 
agitated during 24 hours, the insoluble matter 
being collected on counterbalanced filter papers 
or in a tared filtering crucible and dried at 105°. 
Alkalies and alkaline earths. — Exsiccated ammo- 
nium alum meets the requirements of this test 
under alum, allowance being made for the differ- 
ence in water content. Arsenic, heavy metals, iron. 
— Exsiccated alum meets the requirements of 
these tests under alum, allowance being made for 
the difference in water content. N.F. 

Assay. — A sample of about 500 mg. of exsic- 
cated alum, previously dried at 200° for 4 hours, 
is dissolved in water, filtered if necessary, and 
the aluminum precipitated as described under 
Alum. The weight of the aluminum oxide is mul- 
tiplied by 4.652 to obtain the equivalent weight 
of A1NH4(S04)2, and by 5.066 to obtain the 
weight of A1K(S04)2. N.F. 

Uses. — Exsiccated alum has the same me- 
dicinal properties as ordinary alum, but it is much 
more powerful and irritant and must be employed 
in correspondingly dilute solutions. It has mild 
escharotic properties and is occasionally applied 
to exuberant granulations, preferably diluted with 
inert powders. H 

Storage. — Preserve "in tight containers." N.F. 



54 



Aluminum 



Part I 



ALUMINUM. U.S.P. 

Al (26.98) 



Ft. Aluminium. Gcr. Aluminium. 
Aluminio. 



It. Alluminio. Sp. 



Next to oxygen and silicon, aluminum is (he 
most widely distributed and abundant element on 
earth, comprising about 7.5 per cent of the earth's 
crust. It occurs in nature only in combination. 
Feldspar, mica, zeolite, hornblende, leucite, and 
shales and clays are silicates of aluminum; corun- 
dum, emery, and such gems as the ruby and sap- 
phire are naturally occurring oxides of aluminum. 
Many other gem stones contain aluminum in one 
form or another. Cryolite, NaaAlFe, and bauxite, 
a mixture of hydrated aluminum oxide and hy- 
drated iron oxide, are other compounds of alumi- 
num found in nature; bauxite is the ore commonly 
used for extraction of the element. 

Sir Humphry Davy in 1807 endeavored to ob- 
tain aluminum by electrolysis, but was unsuc- 
cessful. It was obtained by Wohler in 1827 by 
decomposition of anhydrous aluminum chloride 
with potassium. In 1854, Deville succeeded in 
obtaining the pure metal in ingots by decomposing 
aluminum chloride with sodium. The process of 
Deville remained the only practical process for 
its manufacture until 1886, when the Messrs. 
Cowles of Cleveland, Ohio, succeeded in effecting 
the reduction of corundum, the native oxide, by 
charcoal with the aid of a powerful electric cur- 
rent, using large carbon electrodes. This process 
in turn has been practically displaced by that dis- 
covered by Hall, in 1886, while a student at Ober- 
lin College. This is to electrolyze pure alumina 
(aluminum trioxide) dissolved in a bath of melted 
cryolite. The cryolite is continuously regenerated, 
so that by feeding in the pure alumina the process 
can be made continuous. 

Description. — The U.S.P. describes pow- 
dered aluminum as follows: "Aluminum is a very 
fine, free-flowing, silvery powder, free from gritty 
or discolored particles. Aluminum is insoluble in 
water and in alcohol. It is soluble in hydrochloric 
and sulfuric acids, and in solutions of fixed alkali 
hydroxides." U.S.P. The whole metal has a silvery- 
white appearance; its specific gravity is about 2.7, 
its melting point is 659°, its boiling point is 1800°. 
It is ductile, soft, and moderately resistant to 
oxygen. On exposure to air, the metal becomes 
coated with a thin layer of oxide, which serves as 
a protective covering. Aluminum is attacked 
slowly by organic acids. 

It has found wide use in many technical fields 
due primarily to its light weight and relative sta- 
bility. The strength of aluminum is greatly in- 
creased by alloying with copper and magnesium. 
Alloys of this type are magnalium and duralumin. 
When a mixture of powdered aluminum and iron 
oxide is ignited, as by flaming magnesium ribbon, 
a reaction is started which produces a temperature 
of about 3000°, the iron melting and being used 
for welding. Thermite is such a mixture which 
has been employed, among other uses, as an in- 
cendiary in World War I. 

Standards and Tests. — Insoluble matter. — 
Not over 5 per cent is insoluble in dilute hydro- 



chloric acid (1 in 2). Alkalies and earths. — Not 
over 0.5 per cent, when determined by precipi- 
tating the aluminum in the solution obtained in 
the preceding test with ammonia, evaporating the 
filtrate to dryness and igniting the residue. 
Arsenic. — The limit is 10 parts per million. Heavy 
metals. — The limit is 20 parts per million. Iron. — 
The limit is 0.5 per cent. Suitability. — Aluminum 
powder is smooth and unctous, and free from 
gritty particles, when rubbed between the fingers. 
U.S.P. 

Physiological Actions. — Aluminum has very 
feeble physiologic properties. After ingestion very 
little aluminum is absorbed even in the case of 
soluble salts. McGuigan (/. Lab. Clin. Med., 1927, 
12, 790) finds that it is less toxic than iron, and 
Underhill and Peterman (Am. J. Physiol., 1929, 
90, 1) reported that the lethal dose of aluminum 
chloride for various animals ranges from 5 to 7 
Gm. per Kg. after subcutaneous injection; this 
would correspond to a dose for the average man 
of about 8 pounds. Small traces of aluminum are 
found almost always in the tissues and blood 
of man, as well as of the lower animals. (See 
Schwartze, J.A.M.A., 1933, 101, 1722). From 
time to time interested persons have made state- 
ments, usually without much scientific evidence, 
concerning the injurious effects of small quanti- 
ties of aluminum and consequent danger from the 
use of aluminum cooking utensils or alum baking- 
powders. The U. S. Department of Agriculture in 
1914 appointed a committee under the chairman- 
ship of Prof. Ira Remsen to investigate whether 
the use of aluminum baking-powders was injuri- 
ous to the health. As a result of the study of 
previous researches, as well as experimental work, 
they concluded that aluminum, in the quantities 
used in baking-powder, had no injurious effect 
upon the body. Despite the assertions of Doellken 
(Arch. exp. Path. Pharm., 1897, 40) that the re- 
peated injection of aluminum causes degenera- 
tion of the nerves, and the findings of Seibert and 
Wells (Arch. Path., 1929, 8, 230) that such in- 
jections caused anemia, the whole weight of our 
present evidence points toward the innocuousness 
of aluminum kitchenware. For further informa- 
tion on this subject, see J. A.M. A., 1936, 106, 218; 
1951, 146, 477. 

Contact dermatitis in aircraft workers due to 
aluminum or its alloys has been reported. Hall 
(J. A.M. A., 1944, 125, 179) saw 202 cases of con- 
tact dermatitis among 755 employees referred to 
the skin clinic during 6 months from plants em- 
ploying over 6,000 persons. Of the 202 cases, 10 
were due to Dural (aluminum 95 per cent, copper 
3.5 per cent, manganese and magnesium 0.5 per 
cent each, and traces of iron and silica) ; the char- 
acteristics were : scattered, pale-pink, fine papules, 
which were usually excoriated, located on the 
forearms in all cases and on the sides of the neck 
in half the cases; the etilogy was confirmed by 
means of a patch test with the metal which was 
not read until 48 to 72 hours after removal of the 
patch to avoid the immediate irritant effect of the 
metallic particles. Four cases were due to alumi- 
num alone and were distinctly different — evanes- 
cent, wheal-like, extremely pruritic lesions de- 
veloped on the wrists and flexor surface of the 



Part I 



Aluminum Acetate Solution 



55 



forearms during each work period and usually 
cleared up over week ends. 

Like others of the so-called heavy metals, alu- 
minum when combined in an easily ionizable salt, 
such as the sulfate or chloride, acts as an astrin- 
gent. Its insoluble salts are used both as protec- 
tives and adsorbents. The powdered metal or, 
more conveniently, an aluminum paste (q.v.) has 
been employed to protect the skin around intes- 
tinal fistulae from the digestive action of the 
intestinal contents. It is for this use that the 
U.S. P. recognizes aluminum powder. A prepara- 
tion containing finely powdered metallic aluminum 
mixed with glycerin has been employed as a sub- 
stitute for the insoluble salts of bismuth in the 
treatment of gastric ulcers and anal fissures (see 
Sussmann, Ther. Geg., May, 1908). A piece of 
smooth, polished aluminum has been employed as 
a dressing for indolent wounds with success 
(Presse med., 1942, 50, 588). Brown (Am. J. 
Surg., 1948, 76, 594) used aluminum foil as a 
dressing for burns. Buettner (J.A.M.A., 1950, 
144, 737) found that cloth coated with aluminum 
foil provided the best protection from heat for 
fire-fighting equipment. 

Aluminum in the form of the powdered metal 
or the amorphous hydrated alumina is employed 
in the treatment of silicosis (pneumoconiosis). 
The greatly differing incidence of silicosis in dif- 
ferent industries suggested the presence of modi- 
fying factors in addition to the number and size 
of the silica particles in the air. Based on the 
observation of Denny and Robson that small 
amounts of aluminum formed a coating over the 
silica particles which almost completely inhibited 
the solubility of silica and that the addition of 
aluminum powder to silica would prevent the de- 
velopment of silicosis in animals, Crombie, Blais- 
dell and MacPherson (Can. Med. Assoc. J., 1944, 
50, 318) treated 44 employees with evidence of 
silicosis by roentgen examination of the chest, 
some of whom had mild symptoms of pulmonary 
fibrosis, with daily inhalations of powdered alu- 
minum produced in a special ball mill. Inhala- 
tions were increased from 5 minutes to 30 minutes 
daily and continued for about 200 treatments. 
Symptomatic improvement was observed in some 
of the men and none of them showed any progres- 
sion of their silicosis by any criteria whereas 6 of 
9 control cases were definitely worse at the end of 
the year. Bamberger (Ind. Med., 1945, 14, 477) 
and MacGregar (West Virg. M. J., 1945, 41, 229) 
confirm these observations. Although the roentgen 
appearance of silicosis has been reported in asso- 
ciation with exposure to aluminum dust (Arch. 
Gewerbepath. Gewerbehyg., 1941, 11, 102, cited 
in J.A.M.A., 1945, 127, 190), this has not been 
the experience of Crombie and his associates nor 
of others (Gardner et al., J. Indus t. Hyg. Toxicol., 
1944, 26, 211; Hunter et al., Brit. M. J., 1944, 1, 
159). However, bronchial asthma due to alumi- 
num in an employee, who also showed the charac- 
teristic contact dermatitis, has been reported by 
Cotter (/. Indust. Hyg. Toxicol., 1943, 25, 421) 
and by others previously. The therapeutic or pro- 
phylactic use of aluminum powder does not elimi- 
nate the necessity and preferability of dust con- 
trol in industry (Tabershaw, New Eng. J. Med., 



1945, 233, 437). Furthermore, Brown and Van 
Winkle (J. A.M. A., 1949, 140, 1024), in a joint 
report for the Councils on Industrial Health and 
Pharmacy and Chemistry of the American Medi- 
cal Association, concluded that evidence for either 
the safety or efficacy of prophylaxis with alumi- 
num was not available and was not likely to be- 
come available because of the nature of silicosis 
and the problems of industrial exposure. 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

ALUMINUM ACETATE SOLUTION. 

U.S.P. 

Burow's Solution, Liquor Alumini Acetatis 

"Aluminum Acetate Solution yields from each 
100 ml., not less than 1.2 Gm. and not more than 
1.45 Gm. of AI2O3, and not less than 4.24 Gm. 
and not more than 5.11 Gm. of acetic acid 
(C2H4O2), corresponding to not less than 4.8 
Gm. and not more than 5.8 Gm. of aluminum 
acetate (CeHsAlOe)." U.S.P. 

Add 15 ml. of glacial acetic acid to 545 ml. of 
aluminum subacetate solution and sufficient water 
to make 1000 ml. Mix and, if necessary, filter. 
Up to 0.6 per cent of boric acid may be added to 
stabilize the solution (against precipitation of a 
basic compound). Other methods of producing 
the aluminum acetate, as by reaction between 
lead acetate and aluminum sulfate (see U.S.D., 
23rd edition, page 603, for formula), may be 
used but the finished product must meet the 
U.S.P. requirements. Only clear aluminum acetate 
solution may be dispensed. U.S.P. 

Description. — "Aluminum Acetate Solution is 
a clear, colorless liquid having a faint acetous 
odor, and a sweetish, astringent taste. Its specific 
gravity is about 1.022." U.S.P. 

Standards and Tests. — Identification. — Alu- 
minum acetate solution responds to tests for alu- 
minum and for acetate. pH . — The pH of the solu- 
tion is about 4. Heavy metals. — The limit is 10 
parts per million. Limit of boric acid. — After neu- 
tralizing 25 ml. of aluminum acetate solution 
with 0.5 JV sodium hydroxide, using phenolph- 
thalein T.S. as indicator, glycerin is added and 
the resulting strongly ionized complex of boric 
acid is titrated with 0.5 N sodium hydroxide. A 
blank determination is performed omitting the 
aluminum acetate solution, the result of the titra- 
tion of which is subtracted from that required 
for the solution of the sample. Each ml. of the 
difference, expressed as 0.5 N sodium hydroxide, 
represents 30.92 mg. of boric acid (the hydrogen 
equivalent of boric acid in this test is one). 
U.S.P. 

Assay. — For aluminum oxide. — From a sample 
of 10 ml. of aluminum acetate solution the alu- 
minum is precipitated as hydroxide by ammonia 
T.S. in the presence of ammonium chloride. The 
precipitate is collected on a quantitative filter, 
washed with hot distilled water, dried and ignited 
to AI2O3. For acetic acid. — From a 20-ml. sample 
of aluminum acetate solution the acetic acid is dis- 
tilled into a measured excess of 0.5 N sodium hy- 
droxide and the excess of the latter determined by 
titration with 0.5 N sulfuric acid, using phenol- 



56 



Aluminum Acetate Solution 



Part I 



phthalein T.S. as indicator. Each cc. of 0.5 N 
sodium hydroxide represents 30.03 mg. of 
C2H4O2. U.S.P. 

Uses. — Burow's solution, properly diluted, is 
very useful as a wet dressing in the treatment of a 
wide range of dermatologic conditions. It is of par- 
ticular value in treating acute vesicular and 
weeping dermatitis of the eczematous, contact 
type, but may be used on any acute or subacute 
cutaneous inflammation. It acts by a combination 
of detergent, antiseptic, astringent, and heat- 
dispersing effects; Combes (N.Y. State J. Med., 
1940, 40, 37) stressed the importance of its 
buffering action in maintaining normal skin pH 
in the presence of inflammation. Cooper (Am. J. 
Surg., 1948, 75, 475) found the solution of value 
as cleansing, adjuvant therapy in stasis dermatitis 
and ulcers. 

Wet dressings of aluminum acetate solution 
may be utilized in the form of open compresses 
applied intermittently to affected areas, as fixed 
closed dressings (the solution being applied to 
the dressings), or as soaks in acute conditions of 
the hands and feet (contact eczema, acute der- 
matophytosis). For these uses the official alumi- 
num acetate solution should be diluted with 20 
to 30 volumes of water. A combination of alumi- 
num sulfate and calcium acetate, known as 
Domeboro (Dome Chemicals), is supplied in the 
form of effervescent tablets and powders; one 
tablet or powder dissolved in a pint of water 
provides the equivalent of a 1:20 solution of 
aluminum acetate. 

Burow's solution is sometimes incorporated 
in dermatologic lotions, in a concentration of 
about 10 per cent; it is also an ingredient of 
the "1-2-3" paste used in treating acute and 
chronic eczematous dermatoses and containing 
1 part of Burow's solution, 2 parts of hydrophilic 
petrolatum or anhydrous lanolin, and 3 parts of 
zinc oxide paste. 

Aluminum acetate solution has been adminis- 
tered by Ghormley and Hinchey (/. Bone Joint 
Surg., 1944, 26, 811) to patients with malacic 
diseases of bone. The treatment was based on 
studies by Helfet. who used feedings of aluminum 
acetate to diminish phosphorus intake as a sub- 
stitute for a low phosphorus diet, which is nearly 
impossible to achieve when a high calcium intake 
is desired. Improvement was obtained in osteitis 
fibrosa, osteoporosis. Paget's disease, and osteo- 
genesis imperfecta. Their patients were given 
Burow's solution in a vehicle of tolu syrup and 
honey; adequate supplies of milk were given 
daily. H 

Aluminum acetate solution is applied topically, 
commonly being diluted with 10 to 40 volumes of 
water. 

Storage. — Preserve "in tight containers." 
U.S.P. 

ALUMINUM CHLORIDE. U.S.P. 

[Alumini Chloridum] 

"Aluminum Chloride, when dried over sulfuric 
acid for 4 hours, contains not less than 95 per 
cent of AICI3.6H2O." U.S.P. 

Aluminium Chloride. Aluminium Chloratum. Fr. Chlorure 



d'aluminium. Get. Aluminiumchlorid. It. Cloruro di allu- 
minio. Sp. Cloruro de aluminio. 

Aluminum chloride may be prepared by heat- 
ing aluminum in chlorine, or by reacting alumi- 
num hydroxide with hydrochloric acid. 

Description. — "Aluminum Chloride is a 
white or yellowish white, deliquescent, crystalline 
powder. It is nearly odorless, and has a sweet, 
very astringent taste and its solutions are acid to 
litmus paper. One Gm. of Aluminum Chloride 
dissolves in about 0.9 ml. of water and in about 
4 ml. of alcohol. It is soluble in glycerin." U.S.P. 

Standards and Tests. — Identification. — A 1 
in 10 solution of aluminum chloride responds to 
tests for aluminum and for chloride. Sulfate. — 
No turbidity is produced in 1 minute after adding 
0.2 ml. of barium chloride T.S. to 10 ml. of a 1 
in 100 solution of aluminum chloride. Alkalies 
and alkaline earths. — Not more than 0.5 per cent 
of residue is obtained on evaporating the filtrate 
from a solution of aluminum chloride from which 
the aluminum has been precipitated by ammonia 
T.S. Arsenic. — Aluminum chloride meets the re- 
quirements of the test for arsenic. Heavy metals. 
— The limit is 20 parts per million. Iron. — The 
limit is 10 parts per million. U.S.P. 

Assay. — A sample of about 500 mg. of alumi- 
num chloride, previously dried for 4 hours over 
sulfuric acid, is dissolved in water and the alumi- 
num precipitated as explained under Alum. Each 
Gm. of aluminum oxide represents 4.736 Gm. of 
AICI3.6H2O. U.S.P. 

Uses. — Aluminum chloride is employed exter- 
nally as an astringent and antiseptic, especially in 
hyperhidrosis. It is commonly used as a 25 per 
cent solution, applied lightly and only to un- 
broken skin; solutions as dilute as 10 per cent 
are sometimes used. If irritation occurs the 
solution should be washed off. Aluminum chloride 
is an ingredient in many proprietary preparations 
for diminishing local sweating. The salt is no 
longer used internally. 

Storage. — Preserve "in tight containers." 
U.S.P. 

ALUMINUM HYDROXIDE GEL. U.S.P. 

Colloidal Aluminum Hydroxide, Gelatum 
Alumini Hydroxidum 

"Aluminum Hydroxide Gel is a suspension con- 
taining the equivalent of not less than 3.6 per 
cent and not more than 4.4 per cent of aluminum 
oxide (AI2O3), in the form of aluminum hydroxide 
and hydrated oxide. It may contain peppermint 
oil, glycerin, sorbitol, sucrose, saccharin, or other 
suitable agents for flavoring purposes, and it may 
contain sodium benzoate, benzoic acid, or other 
suitable agents, in a total amount not exceeding 
0.5 per cent, as a preservative." U.S.P. 

Sp. Hidrato de Aluminio Gelatinado. 

The U.S.P. LX recognized under the title Alu- 
mini Hydroxidum the precipitate formed by mix- 
ing solutions of sodium carbonate and of alum. 
This was a white, bulky, amorphous powder, 
relatively inefficient as a gastric antacid. It was 
used as a protective and mild astringent in the 
treatment of irritated conditions of the skin in 
much the same way as zinc oxide is employed. 



Part I 



Aluminum Hydroxide Gel 57 



Aluminum hydroxide gel may be prepared by a 
number of methods; the products vary widely in 
viscosity and particle size, and hence in the rate 
of solution in acids. It is known that such factors 
as the degree of supersaturation with respect to 
aluminum hydroxide, the pH during precipitation, 
the temperature, and the nature and concentration 
of by-product ions present are important in deter- 
mining the physical and, to an extent, the chemical 
properties of the aluminum hydroxide. 

While details of the manufacturing processes 
are not disclosed one manufacturer of an elegant 
preparation reacts aluminum chloride with a solu- 
tion containing sodium carbonate and sodium 
bicarbonate, the product of this reaction is re- 
ported to be mixed with the precipitate obtained 
by reacting solutions of aluminum chloride and of 
ammonia. The mixed magma is dialyzed in canvas 
bags, the product is mixed with some glycerin, so- 
dium benzoate is added, and the mixture passed 
through a colloid mill. 

This product is available under its official name 
and under several trade names including: Ampho- 
jel (Wyeth), Creamalin (Winthrop-Stearns), and 
Vanogel (Vanpelt & Brown). Hydrogel (Breon) 
contains more aluminum hydroxide than does the 
official product and Flaagel (Breon) differs in 
that it contains color and orange flavor. 

Description. — "Aluminum Hydroxide Gel is 
a white, viscous suspension, from which small 
amounts of clear liquid may separate on stand- 
ing." U.S.P. 

Standards and Tests. — Identification. — A so- 
lution of aluminum hydroxide gel in hydrochloric 
acid responds to tests for aluminum. Reaction. — 
Both red and blue litmus paper are slightly af- 
fected by aluminum hydroxide gel, but phenol- 
phthalein T.S. is not reddened. Acid-consuming 
capacity. — About 1.5 ml. of the gel, accurately 
weighed, is reacted with SO ml. of 0.1 N hydro- 
chloric acid, at 37.5° for 1 hour; the excess acid 
is titrated with 0.1 N sodium hydroxide, using 
bromophenol blue T.S. as indicator. Each Gm. 
of gel requires not less than 12.5 ml. and not 
more than 25 ml. of 0.1 N acid. Chloride. — The 
limit is 0.28 per cent. Sulfate. — The limit is 500 
parts per million. Arsenic. — The limit is 0.8 part 
per million. Heavy metals. — The limit is 5 parts 
per million. U.S.P. 

Assay. — About 5 Gm. of gel, accurately 
weighed, is dissolved in a solution of hydrochloric 
acid and the aluminum ion precipitated as hy- 
droxide by ammonia T.S. The precipitate is ig- 
nited to constant weight as AI2O3. U.S.P. 

Uses. — Colloidal aluminum hydroxide is used 
almost exclusively as a gastric antacid, especially 
in the treatment of peptic ulcer. In the stomach 
it neutralizes hydrochloric acid, forming aluminum 
chloride and water. Schiffrin and Komarov (Am. 
J. Digest. Dis., 1941, 8, 215) reported that the 
aluminum ion inhibits pepsin activity even in acid 
solution. No more hydroxyl ions are liberated 
than are necessary for neutralization of the acid. 
Each Gm. of the official suspension will neutralize 
to pH 3.5 from 12.5 to 25 ml. of gastric juice 
having an acidity corresponding to 0.1 N hydro- 
chloric acid. The rate of this neutralization is 
comparable to that of milk or egg, requiring 



from 5 to 15 minutes. It acts more slowly than 
the soluble alkalies, such as sodium bicarbonate 
which rapidly neutralizes acid to pH 7 or higher 
(Adams, Arch. Int. Med., 1939, 63, 1030). In 
a study of gastric antacids to determine the rate 
and extent of neutralization of 0.1 N hydro- 
chloric acid, added at 30 minute intervals to 
simulate continuous gastric secretion, Hammar- 
lund and Rising (J.A.Ph.A., 1949, 38, 586) 
found that aluminum hydroxide gradually raises 
the pH to about 4, maintains this value for 2 
or 3 hours, and then gradually loses its antacid 
effect, while magnesium trisilicate rather more 
quickly raises the pH to 5 or 6 but main- 
tains this for only a short time before its antacid 
effect is almost completely and abruptly spent. 
In the alkaline portion of the intestine the alumi- 
num chloride reacts to produce insoluble alu- 
minum compounds while releasing an equivalent 
amount of chloride which is restored to the 
system. 

Aluminum hydroxide possesses adsorbent prop- 
erties toward many substances. Because of its 
lack of alkaline character it does not produce a 
rebound secretion of hydrochloric acid in the 
stomach, as is the case with the soluble alkalies. 
Because of its insolubility it is practically unab- 
sorbable from the alimentary tract and hence 
there is no danger of disturbing the pH balance of 
the system, of impairing renal function, or of 
having toxic effects (Kirsner, Am. J. Digest. Dis., 
1941, 8, 160). It interferes, however, with the 
absorption of phosphates from the intestine and in 
the presence of a low phosphorus diet may cause 
a deficiency (Fauley et al., Arch. Int. Med., 
1941, 67, 563). It is prescribed for this purpose 
in the treatment of renal rickets, chronic uremia 
and phosphatic renal calculi (Shorr and Carter, 
1950, 144, 1549). Page and Page (Obstet. Gynec, 
1953, 1, 94) relieved the muscular leg cramps 
which occurred in about half of their well-fed 
pregnant patients by prescribing 0.6 Gm. of alu- 
minum hydroxide three times daily or by re- 
ducing the consumption of milk, which provides 
an excess of phosphorus in relation to calcium. 
It appears not to interfere with absorption of 
amino acids, ascorbic acid, glucose, and neutral 
fat (Hoffman and Dyniewicz, Gastroenterology , 
1946, 6, 50). Some clinicians have claimed excel- 
lent results in various forms of enteritis due to 
its adsorbent oower. Eyerly and Breuhaus 
(J.A.M.A., 1937, 109, 191) reported favorably 
on the use of enemas of aluminum hydroxide gel 
and kaolin in ulcerative colitis. 

The most important medicinal use of aluminum 
hydroxide is in the treatment of peptic ulcer, in 
which the persistence of its antacid effect is of 
especial importance, but it appears also to act as 
a protecitve in these cases and to exercise some 
other beneficial, perhaps astringent, action beyond 
that of merely correcting the acidity; it is prob- 
able that it has a protective action on the raw 
surface. For literature on the use of this drug see 
the report of the Council on Pharmacy, J.A.M.A., 
1941, 117, 1356. Collins (J.A.M.A., 1945, 127, 
899) has reported the satisfactory use of alumi- 
num hydroxide gel in the management of 3,000 
patients with peptic ulcer over a period of many 



58 



Aluminum Hydroxide Gel 



Part I 



years (see also Rossett et al, Ann. Int. Med., 
1952, 36, 98). The more prolonged and effective 
action of aluminum hydroxide enabled the ma- 
jority of patients to follow a regimen compatible 
with their occupations, although general hygienic 
measures, diet and alleviation of mental tension 
could not be neglected. Its constipating action 
in some cases is undesirable; the simultaneous 
use of laxatives may be required. The tendency 
of the peptic ulcer patient to constipation is fa- 
vored by the low-residue, bland diet usually 
prescribed. Batterman and Ehrenfeld {Gastroen- 
terology, 1947, 9, 141) reported the incidence 
of constipation with various antacids as follows: 
non-reactive aluminum hydroxide gels, 30 to 35 
per cent; reactive aluminum hydroxide gels, 16 
to 33 per cent; magnesium trisilicate. 14 to 15 
per cent. Kirsner et al. (Ann. Int. Med., 1951, 
35, 7S5) pointed out that no antacid in a single 
dose was capable of neutralizing the night-time 
hypersecretion of the duodenal ulcer patient. 
For cases refractory- to usual medical man- 
agement Winkelstein and Hollander (Surgery, 
1945, 17, 696) and others employed with success 
a continuous intragastric drip of aluminum hy- 
droxide gel or a mixture of milk and sodium 
bicarbonate. Woldman (Am. J. Digest. Dis., 
1941, 8, 39) reported that the continuous method 
of administration was particularly beneficial in 
bleeding peptic ulcer. In their most successful 
management of the bleeding peptic ulcer patient, 
Dunphy and Gray (Mod. Med., March 1, 1952, 
p. 90) employed hourly feedings of 100 ml. of 
warm milk and cream with 10 ml. of aluminum 
hydroxide gel every hour during the day and 
double these quantities even - 2 hours during 
the night along with phenobarbital, atropine, 
vitamins, and blood replacement, with operation 
if shock was not corrected by transfusions. Binder 
and Paul (Am. J. Digest. Dis., 1952, 19, 278) 
reported good results in the bleeding case with a 
similar medical management. Cantor et al. (Am. 
J. Surg., 1950. 80, SS3) gave gelfoam and throm- 
bin by mouth to form a clot in such cases and 
used aluminum hydroxide gel to prevent diges- 
tion of the thrombin and the clot. 

Howard (U. S. Nov. M. Bull, 1945, 44, 1047) 
reported prompt relief and rapid healing from 
local application of aluminum hydroxide gel to 
a variety of skin conditions, such as miliaria 
rubra, tinea cruris or circinata, weeping eczema- 
tous lesions, impetigo and epidermophytosis. 
Friedman et al. (Am. J. Digest. Dis., 1948, 15, 
57) effectively employed a paste in moist, but 
not in dry. types of pruritus ani. 

Aluminum hydroxide gel has been used as a 
vehicle to increase the absorption of orally ad- 
ministered penicillin (J. A.M. A., 1945, 128,' 845; 
1945, 129, 315). Administration of aluminum 
hydroxide with anticholinergic drugs, such as atro- 
pine sulfate, given by mouth to animals, was 
found by Seifter et al. (I. Pharmacol., 1952, 105, 
96) to retard the absorption of the latter but to 
prolong its action considerably. Clinical studies 
by Berkowitz (Antibiot. Chemother., 1953. 3, 
618) demonstrated that the addition of aluminum 
hydroxide gel to a triple sulfonamide mixture 
increased and prolonged the concentration of 



sulfonamide in the blood. Simultaneous adminis- 
tration of aluminum hydroxide with aminophyl- 
line decreased the incidence of gastrointestinal 
disturbances to such a degree that sufficient of 
the latter compound could be given orally to at- 
tain levels of theophylline in the blood which 
are comparable to those obtained by intravenous 
administration of aminophylline (Cronheim et al., 
Postgrad. Med., 1953, 13, 432); the aluminum 
hydroxide appears not to alter the rate or the 
degree of absorption of the aminophylline. With 
chlortetracycline (Aureomycin > , aluminum hy- 
droxide gel relieves the frequent gastrointestinal 
disturbances but it also decreases the blood con- 
centration of the antibiotic (Waisbren and others, 
J.A.M.A., 1949, 141, 938; Boger et al, J. Phila. 
Gen. Hosp., 1950, 1, 3) and changes its effect 
on fecal urobilinogen and fecal bacterial flora 
(Hayford and Waisbren. Surgery, 1952, 31, 361). S 

Dose. — The usual dose of aluminum hydroxide 
gel is 8 ml. (2 fluidrachms), with half a glass of 
water, 3 to 6 times daily, about one hour after 
meals and at bedtime. It may be taken as fre- 
quently as every two hours. The range of dose is 
4 to 30 ml.; generally not over 60 ml. is to be 
taken in 24 hours. 

Storage. — Preserve '"in tight containers and 
avoid freezing/' U.S.P. 

DRIED ALUMINUM HYDROXIDE 
GEL. U.S.P. 

Gelatum Alumini Hydroxidi Siccum 

''Dried Aluminum Hydroxide Gel yields not 
less than 50 per cent of aluminum oxide (AI2O3)." 
U.S.P. 

Sp. Hidrato de Aluminio Gclatinado Seco. 

Dried aluminum hydroxide gel is prepared by 
drying, at not too high temperature, the magma 
of aluminum hydroxide obtained in preparing 
the liquid gel (see preceding monograph) prior 
to addition of glycerin or preservative. Products 
on the market differ widely in bulk and rate of 
solution because of variation in the temperature 
and rate of drying, as well as variation in the 
factors discussed under Aluminum Hydroxide Gel. 

Description. — "Dried Aluminum Hydroxide 
Gel is a white, odorless, tasteless, amorphous 
powder. Dried Aluminum Hydroxide Gel is in- 
soluble in water and in alcohol. It is soluble in 
diluted mineral acids and in solutions of fixed 
alkali hydroxides.'' U.S.P. 

Standards and Tests. — Identification. — A so- 
lution of 500 mg. of dried aluminum hydroxide 
gel in 10 ml. of diluted hydrochloric acid responds 
to tests for aluminum. Reaction. — The filtrate 
from a suspension of 1 Gm. of dried gel in 25 ml. 
of water is neutral to litmus paper. Acid-con- 
suming capacity. — Each Gm. of dried aluminum 
hydroxide gel requires not less than 250 ml. of 
0.1 N hydrochloric acid (see this test under 
Aluminum Hydroxide Gel). Chloride. — The limit 
is 0.84 per cent. Sulfate. — The limit is 0.6 per 
cent. Arsenic and heavy metals. — Dried aluminum 
hydroxide gel meets the requirements of the cor- 
responding tests under Aluminum Hydroxide Gel, 
allowance being made for the difference in content 
of AI2O3. U.S.P. 



Part I 



Aluminum Phosphate Gel 59 



Assay. — A sample of about 400 mg. of dried 
gel is assayed in a manner similar to that sum- 
marized under the assay for Aluminum Hydroxide 
Gel. U.S.P. 

Uses. — In the form of tablets this is a con- 
venient method of administering aluminum hy- 
droxide gel. The following are proprietary names 
for the tablets: Alugel (Cole), Amphojel 
(Wyeth), Creamalin (Winthrop), Drydgel (Fair- 
child), and Vanogel (Vanpelt & Brown). For an 
account of its therapeutic uses see under Alumi- 
num Hydroxide Gel. The antacid action of the 
dry form is less rapid and efficient than that of 
the gel. Tablets should probably be chewed for 
best results. 

The usual dose is 300 mg. (approximately 5 
grains) 4 times daily; the range of dose is 300 mg. 
to 2.4 Gm. 

Storage. — Preserve "in tight containers." 
U.S.P. 

ALUMINUM PASTE. U.S.P. 

"Aluminum Paste contains not less than 9 per 
cent and not more than 10 per cent of Al." U.S.P. 

Levigate 100 Gm. of aluminum, in very fine 
powder, with 50 Gm. of liquid petrolatum to a 
smooth paste and then incorporate this mixture 
with 850 Gm. of zinc oxide ointment. U.S.P. 

Assay. — A 1-Gm. portion of aluminum paste 
is heated with a mixture of sulfuric and nitric 
acids to oxidize as much of the fatty base as pos- 
sible, while also dissolving the aluminum. The pH 
of the liquid is adjusted to 2.5 and the zinc is 
precipitated as sulfide. Aluminum in the filtrate 
is precipitated as hydrous aluminum oxide by add- 
ing ammonium hydroxide, and the precipitate is 
finally weighed as AI2O3. The weight of Al in the 
sample is calculated by multiplying the weight 
of the oxide by 0.5292. U.S.P. 

Use. — As mentioned in the article on alumi- 
num, this paste is a convenient means of applying 
the powdered metal around intestinal fistulae to 
protect the surrounding skin against the digestive 
action of the intestinal contents. 

Storage. — Preserve "in well-closed containers, 
and avoid prolonged exposure to temperatures 
above 30°." U.S.P. 

ALUMINUM PHOSPHATE GEL. U.S.P. 

[Gelatum Alumini Phosphatis] 

"Aluminum Phosphate Gel is a water suspen- 
sion containing not less than 3.8 per cent and not 
more than 4.5 per cent of aluminum phosphate 
(AIPO4). It may contain peppermint oil, glycerin, 
sorbitol, sucrose, saccharin, or other suitable 
agents for flavoring purposes, and it may contain 
sodium benzoate, benzoic acid, or other suitable 
agents, in an amount not exceeding 0.5 per cent, 
as a preservative." U.S.P. 

Phosphaljel (Wyeth). Sp. Gel de Fosfato de Aluminio. 

Aluminum phosphate gel may be prepared by 
the interaction of an aluminum salt with a phos- 
phate; the product, like aluminum hydroxide gel, 
varies in viscosity and particle size depending on 
the pH of the reaction mixture, the temperature, 
and the concentration and the particular salts 



used as the source of the interacting ions. After 
precipitation of the aluminum phosphate the 
product is dialyzed, mixed with one or more of 
the substances officially permitted to be used for 
stabilizing, preserving and flavoring purposes, 
and passed through a colloid mill. 

Description. — "Aluminum Phosphate Gel is 
a white, viscous suspension from which small 
amounts of water may separate on standing." 
U.S.P. 

Standards and Tests. — Identification. — (1) 
A solution of the gel in hydrochloric acid responds 
to tests for Aluminum. (2) A solution of the gel 
in diluted nitric acid responds to tests for phos- 
phate. pH — The pH of the gel, at 25°, is be- 
tween 6.0 and 7.2. Reaction rate. — A mixture of 
30 ml. of 0.1 N hydrochloric acid and 6 Gm. of 
gel, heated at 37° for 15 minutes, has a pH be- 
tween 2.0 and 2.5. Chloride. — Not over 0.16 
per cent. Soluble phosphate. — Not over 700 parts 
per million, calculated as PO-i. Sulfate. — Not 
over 500 parts per million. Arsenic. — Not over 
0.8 part per million. Heavy metals. — The limit is 
5 parts per million. Acid-consuming capacity. — 
About 250 mg. of the gel, accurately weighed, is 
digested with 30 ml. of 0.1 N hydrochloric acid 
at 37° for 30 minutes; the excess acid is titrated 
with 0.1 A 7 sodium hydroxide, using thymol blue 
T.S. and titrating to a pH of 2.5. Each Gm. of gel 
requires not less than 5 and not more than 9 ml. 
of 0.1 A 7 acid. U.S.P. 

Assay. — A 20 Gm. portion of gel is dissolved 
in nitric acid and diluted to 100 ml. with distilled 
water. From a 10-ml. portion of this solution the 
phosphate is precipitated as ammonium phos- 
phomolybdate with ammonium molybdate T.S. 
The precipitate is filtered, washed first with a 
nitric acid solution, then with 1 per cent potas- 
sium nitrate and dissolved in 50 ml. of 0.5 N 
sodium hydroxide; the excess of alkali is titrated 
with 0.5 N sulfuric acid, using phenolphthalein 
T.S. as indicator. The reaction of ammonium 
phosphomolybdate and sodium hydroxide may 
be represented by the following equation: 

(NH.4) 3 P04.12Mo03 + 23NaOH -* 

llNa 2 Mo04 + (NH.4)2Mo0 4 + 

NaNH.4HP0 4 + IIH2O 

from which it is apparent that the equivalent 
weight of AIPO4 is ^3 of its molecular weight, 
one molecule of ammonium phosphomolybdate 
being precipitated for each molecule of aluminum 
phosphate undergoing reaction. Each ml. of 
0.5 N sodium hydroxide represents 2.651 mg. of 
AIPO4. U.S.P. 

Uses. — Aluminum phosphate gel is employed 
in the treatment of peptic ulcer and is particu- 
larly advocated for the patient with postoperative, 
jejunal (marginal) ulcer (Fauley et. al., Arch. 
Int. Med., 1941, 67, 563; Collins, J. A.M. A., 
1945, 127, 899). Whereas aluminum hydroxide 
failed to prevent the development of postoperative 
jejunal ulcer in Mann-Williamson dogs in which 
there is a relative deficiency of bile and pancreatic 
juice, aluminum phosphate gel was shown to be 
effective both as a preventive and a therapeutic 
agent in such dogs. Clinical experience has con- 
firmed the superiority of aluminum phosphate 



60 



Aluminum Phosphate Gel 



Part I 



over aluminum hydroxide in the management of 
peptic ulcer in patients who have a deficiency of 
pancreatic juice, a chronic diarrhea or a dietary 
deficiency in phosphorus. Lichstein et al. (Am. J. 
Digest. Dis., 1945, 12, 65) reported good results 
in patients with uncomplicated peptic ulcer and 
bleeding peptic ulcer. 

The range of dose is 15 to 30 ml. (approxi- 
mately 4 to 8 fluidrachms), alone or with a little 
water, as frequently as even' 2 hours if necessary. 
The total dose in 24 hours usually does not 
exceed 100 ml. 

Storage. — Preserve ''in tight containers." 
U.S.P. 



ALUMINUM SUBACETATE SOLU- 
TION. U.S.P. 

Liquor Alumini Subacetatis 

"Aluminum Subacetate Solution yields, from 
each 100 ml., not /less than 2.30 Gm. and not 
more than 2.60 Gm. of aluminum oxide (AI2O3), 
and not less than 5.43 Gm. and not more than 
6.13 Gm. of acetic acid (C2H4O2)." U.S.P. 

Liquor Aluminii Acetici (Ger., It.). Fr. Solution d'acetate 
d'aluniinium. Ger. Aluminiumazetatlbsung. It. Acetato di 
alluminio liquido. 

Dissolve 160 Gm. of aluminum sulfate in 600 
ml. of water, filter the solution, and gradually add 
70 Gm. of precipitated calcium carbonate, in sev- 
eral portions, with constant stirring. Now slowly 
add 160 ml. of acetic acid, mix, and set the mix- 
ture aside for 24 hours. Filter the mixture through 
a Buchner funnel, wash the magma on the filter 
with small portions of cold water until the filtrate 
measures 1000 ml. The solution may be stabilized 
(against precipitation) by the addition of not 
more than 0.9 per cent of boric acid. Other 
methods of producing the aluminum subacetate 
may be used but the finished product must meet 
the U.S.P. requirements. U.S.P. 

Description. — ''Aluminum Subacetate Solu- 
tion is a clear, colorless, or faintly yellow liquid, 
having an acetous odor and an acid reaction to 
litmus. It gradually becomes turbid on continued 
standing, due to separation of a more basic salt." 
U.S.P. 

Standards and Tests. — Identification. — 
Aluminum subacetate solution responds to tests 
for aluminum and for acetate. Limit for boric 
acid. — This test is performed as directed under 
Aluminum Acetate Solution. U.S.P. 

Assay. — The assay for aluminum oxide and 
that for acetic acid are performed as directed 
under Aluminum Acetate Solution. U.S.P. 

Uses. — Aluminum subacetate solution is use- 
ful as an astringent and antiseptic wash. Diluted 
with 20 to 40 volumes of water it is employed as 
a wet dressing in acute, vesicular and exudative 
eczematous conditions of the skin; occasionally 
somewhat stronger solutions are applied. It was 
formerly used as a gargle for local treatment of 
inflamed conditions of the throat. 

Storage. — Preserve "in tight containers." 
US.P. 

Off. Prep. — Aluminum Acetate Solution, 
US.P. 



ALUMINUM SULFATE. U.S.P. 

[Alumini Sulfas] 

"Aluminum Sulfate contains an amount of 
Ab(S04)3 equivalent to not less than 99.5 per 
cent and not more than 112 per cent of 
Al 2 (S04) 3 .18HoO." US.P. 

Aluminium Sulfate; Concentrated Alum; Pearl or Pickle 
Alum. Aluminium Sulfuricum; Sulfas Aluminicus; Alum- 
inii Sulphas. Fr. Sulfate d'aluminium; Sulfate d'alumine 
pur. Ger. Aluminiumsulfat ; Schwefelsaures Aluminium; 
Schwefelsaure Tonerde. It. Solfato di alluminio. Up. 
Sulfato de aluminio. 

This salt may be manufactured by various 
methods (see U.S.D., 19th ed.. p. 124) as, for ex- 
ample, by dissolving aluminum hydroxide in sul- 
furic acid, but is now obtained chiefly as one of 
the by-products in the manufacture of soda from 
cryolite or from bauxite. 

Description. — "Aluminum Sulfate occurs as a 
white crystalline powder, as shining plates, or as 
crystalline fragments, and is stable in air. It is 
odorless, and has a sweet taste, becoming mildly 
astringent. Its solutions are acid to litmus. One 
Gm. of Aluminum Sulfate dissolves in about 1 ml. 
of water. It is insoluble in alcohol." US.P. 

Standards and Tests. — Identification. — A 1 
in 10 aqueous solution of aluminum sulfate re- 
sponds to tests for aluminum and for sulfate. 
pH. — The pH of a 1 in 20 solution is not less 
than 2.9. Alkalies and alkaline earths. — Not over 
0.4 per cent of residue is obtained on evaporating 
the filtrate from a solution of aluminum sulfate 
from which the aluminum has been precipitated 
by ammonia T.S. Ammonium salts. — Ammonia is 
not evolved on heating 1 Gm. of aluminum sulfate 
with 10 ml. of sodium hydroxide T.S. Arsenic. — 
Aluminum sulfate meets the requirements of the 
test for arsenic. Heavy metals. — The limit is 40 
parts per million. Iron. — A blue color is not pro- 
duced immediately on adding 0.3 ml. of potassium 
ferrocyanide T.S. to 20 ml. of a 1 in 150 solution 
of aluminum sulfate. U.S.P. 

Assay. — A sample of about 500 mg. of alumi- 
num sulfate is assayed as explained under Alum. 
Each Gm. of aluminum oxide represents 6.536 
Gm. of Ai 2 (S04)3.18H 2 0. N.F. 

Uses. — Aluminum sulfate has medicinal prop- 
erties very similar to those of alum. In 15 per 
cent concentration it is used in perspiration- 
inhibiting creams ; it may be used with aluminum 
chloride in liquid deodorants. It has been em- 
ployed in aqueous solution (about 4 or 5 per 
cent) as an antiseptic, detergent application to 
foul ulcers, and as an injection in fetid leukor- 
rhea. In 10 per cent aqueous solution it was used 
by Deuschle (Cincinnati M. J., 1943, 23, 578) 
in sterilization of shallow dental cavities and the 
alveolus after tooth extraction, the area being 
packed and the solution dispersed by the passage 
of a 2.5 milliampere galvanic current for 10 min- 
utes through the saturated pack. Solution of 
aluminum sulfate is capable of dissolving a con- 
siderable quantity of freshly precipitated alumi- 
num hydroxide. Such a solution, impregnated 
with benzoin, has been used as a hemostatic and 
as a vaginal douche in leukorrhea, under the 
name of benzoinated solution of alumina (for 



Part I 



Aminacrine Hydrochloride 61 



method of preparation see U.S.D. 24th ed., p. 58). 
It resembles the styptic liquid of Pagliari. 

Solutions of aluminum sulfate in water are 
commonly used, by local application, in a con- 
centration of 5 to 25 per cent, |v] 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

Off. Prep. — Aluminum Subacetate Solution, 
U.S.P. 

AMARANTH. U.S.P. 

F.D. and C. Red No. 2, [Amaranthum] 



Nq0 3 S 




N=N 




S0 3 Na 



"Amaranth contains not less than 94 per cent 
of C2oHnN2Na30ioS3, calculated on the dried 
basis." U.S.P. 

Amaranth Color; Azo Acid Rubin 2 B; Fast Red D; 
Bordeaux S. Sp. Amaranto. 

One of the products obtained in the sulfonation 
of betanaphthol is 2-naphthol-3,6-disulfonic acid, 
a dye intermediate known as R-acid, from the red- 
dish color of its azo dye derivatives. By coupling 
R-acid with the diazo derivative of naphthionic 
acid (l-naphthylamine-4-sulfonic acid) there re- 
sults the l-(4-sulfo-l-naphthylazo)-2-naphthol- 
3,6-disulfonic acid, of which amaranth is the tri- 
sodium salt. 

Description. — "Amaranth occurs as a dark 
red brown powder. One Gm. of Amaranth dis- 
solves in about 15 ml. of water; it is very slightly 
soluble in alcohol." U.S.P. 

Standards and Tests. — Identification. — (1) 
The color of a 1 in 100 solution of amaranth, 
when viewed through a depth of 1 cm., is vivid 
red; it is not appreciably changed on adding hy- 
drochloric acid, but is intensified on adding sodium 
hydroxide T.S. (2) About 50 mg. of amaranth 
and 200 mg. of powdered sodium hydroxide is 
fused by heating in a small test tube. On adding 
0.5 ml. of water to the cooled residue, then a 
moderate excess of diluted hydrochloric acid, and 
warming, sulfur dioxide is evolved, which may be 
recognized by its odor and also by testing the 
vapor with starch iodate paper. Loss on drying. — 
Not over 10 per cent, when dried at 120° to con- 
stant weight. Water-insoluble substances. — Not 
over 0.5 per cent. Metals precipitated by am- 
monia, ammonium oxalate and phosphate. — Not 
more than approximately 1 per cent. Ether- 
extractable substances. — Not over 0.2 per cent. 
U.S.P. 

Assay. — About 350 mg. of amaranth is dis- 
solved in water, sodium citrate is added, and the 
solution is titrated with 0.1 N titanium trichlo- 
ride, at boiling temperature, which reduces the 
dye to a colorless or practically colorless deriva- 



tive. Each ml. of 0.1 N titanium trichloride repre- 
sents 15.11 mg. of C2oHuN2Na30ioS3. U.S.P. 

Uses. — Amaranth is commonly used in the 
dyeing of wool and silk, being an exceptionally 
fast, light color. Because of its comparatively 
innocuous character it is also included in the 
U. S. Government list of certified colors for foods, 
drugs, and cosmetics. It holds its color fairly well 
in either acid or alkaline solutions. For studies of 
its pharmaceutical uses see Pharm. J., 1936, 136, 
233, 458, and /. A. Ph. A. Prac. Ed., 1941, 2, 398. 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

AMARANTH SOLUTION. U.S.P. 

Liquor Amaranthi 

Dissolve 1 Gm. of amaranth in sufficient puri- 
fied water to make 100 ml. U.S.P. 

Description. — "Amaranth Solution is a clear, 
vivid red liquid, having but a slight odor." U.S.P. 

Storage. — Preserve "in tight, light-resistant 
containers." U.S.P. 

COMPOUND AMARANTH SOLUTION. 

N.F. 

Dissolve 100 Gm. of caramel in 500 ml. of 
purified water, add 90 ml. of amaranth solution, 
250 ml. of alcohol, and enough purified water to 
make the product measure 1000 ml.; mix well. 
N.F. 

Alcohol Content. — From 22 to 25 per cent, 
by volume, of C2H5OH. N.F. 

This solution is used as a color in several N.F. 
preparations; it replaces the compound cudbear 
tincture long used similarly but which varied to 
some extent in tinctorial power. 

Storage. — Preserve "in tight, light-resistant 
containers." N.F. 

AMINACRINE HYDROCHLORIDE. 
B.P. 

Aminacrinae Hydrochloridum 



HCI.H 2 



This antiseptic dye is referred to in the Ameri- 
can literature as 9-aminoacridine hydrochloride, 
but the B.P. describes it as 5-aminoacridine hydro- 
chloride monohydrate, containing not less than 
98.5 per cent of C13H10N2.HCI calculated with 
reference to the substance dried to constant weight 
at 100° at a pressure not exceeding 5 mm. of 
mercury. The substance may be prepared by the 
reaction of N-phenylanthranilic acid with phos- 
phorus oxychloride, then reacting the product with 
ammonium carbonate in phenol. 

Description. — Aminacrine hydrochloride oc- 
curs as a pale yellow, crystalline, odorless powder, 
having a bitter taste. It is soluble in 300 parts of 
water, at 20°; it is soluble in 90 per cent alcohol, 
also in glycerin; at 20° it is soluble in 2000 parts 
of isotonic sodium chloride solution; it is almost 
insoluble in ether and in chloroform. 




62 



Aminacrine Hydrochloride 



Part I 



Standards and Tests. — Identification. — (1) 
A saturated aqueous solution is pale yellow, ex- 
hibiting a greenish-blue fluorescence; a very di- 
lute solution has a powerful blue fluorescence. 
(2) Aminacrine, liberated by the addition of alkali 
to a solution of the salt and dried at 105° after 
recrystallization from dilute alcohol, melts at 
about 235°. (3) The salt responds to tests char- 
acteristic of chlorides. Acidity. — The pH of a 0.2 
per cent (w/v) solution is between 5.0 and 6.5. 
Loss on drying. — Not more than 8.0 per cent. 
Sulfated ash. — Not more than 0.2 per cent. 

Assay. — The assay, using about 500 mg. of 
sample, is identical with that specified for Pro- 
flavine Hemisuljate. Each ml. of 0.1 M potassium 
ferricyanide represnts 69.21 mg. of C13H10N2.- 
HC1, this equivalent being based on the reaction 
of three molecules of aminacrine hydrochloride 
with one molecule of potassium ferricyanide. 

Uses. — In vitro tests have demonstrated that 
the bacteriostatic and bactericidal powers of 
aminacrine hydrochloride are slightly greater than 
those of proflavine; the toxicity, when injected 
subcutaneously into mice, is midway between that 
of proflavine and of acriflavine (Rubbo et al., 
Brit. J. Exp. Path., 1942, 23, 69). The same in- 
vestigators concluded that it is only slightly more 
toxic to human polymorphonuclear leukocytes 
than is proflavine. Russell and Falconer {Lancet, 
1943, 244, 580) showed that an isotonic 1:1000 
solution, buffered at pH 6.2, was harmless when 
applied to exposed rabbit's brain tissue, while the 
same concentration of acriflavine caused hemor- 
rhage and necrosis. After an intensive study of 
the bacteriological and pharmacological proper- 
ties, Ungar and Robinson {Lancet, 1943, 245, 
285; /. Pharmacol., 1944, 80, 217) concluded that 
it was an effective antiseptic having certain ad- 
vantages over acriflavine and proflavine. The hy- 
drochloride, in powder form, is the least inhibitory 
to healing of wounds of any of the acridine anti- 
septics, though Russell and Falconer (loc. cit.) 
and Selbie and Mcintosh (/. Path. Bad., 1943, 
55, 477) could not recommend the use, in powder 
form, of any of the salts of acridine antiseptics 
for prophylactic treatment of fresh wounds. 

Poate {Lancet, 1944, 247, 238; Med. J. Aus- 
tralia, 1944, 1, 242) controlled sepsis in wounds 
in all but 5 out of 120 cases by irrigation with a 
1:1000 solution, with an emulsion, or with a 
powder containing 10 to 40 parts of sulfanilamide 
to 1 part of the acridine compound. The solution 
appeared to be particularly effective against hemo- 
lytic staphylococci; against pyocyaneus infection 
a 1:1000 solution in 2 per cent acetic acid was 
used. Effective sterilization of skin, prior to sur- 
gical operation, by application of a 1 per cent 
solution in 50 per cent alcohol, was reported by 
Bonney and Sandeman-Allen {Brit. M. J., 1944, 
2, 210). Arden {Med. J. Australia, 1945, 32, 486) 
preferred local application of 9-aminoacridine hy- 
drochloride {Monocrine) to excision of contami- 
nated wounds, even when brain tissue was in- 
volved. 

Nemir {Arch. Surg., 1951, 62, 493) employed 
solutions containing 0.05 to 0.5 mg. per ml. in 
peritoneal exudate following soiling with bowel 
contents; the results were superior to those ob- 



tained with 1 unit of penicillin and 10 units of 
streptomycin per ml. or with 0.1 mg. of sulfa- 
diazine per ml. In nontoxic concentrations amina- 
crine hydrochloride inhibited CI. welchii, E. coli, 
Staph, aureus, and some streptococci. As men- 
tioned under Sulfanilamide, a vaginal cream con- 
taining 0.2 per cent aminacrine hydrochloride, 15 
per cent of sulfanilamide, 2 per cent of allantoin, 
and lactose, in a water-miscible base buffered with 
lactic acid to pH 4.5, has been used effectively in 
bacterial cervicitis and vaginitis, Trichomonas 
vaginalis vaginitis, and in some cases of monilial 
vaginitis (Warner, N. Y. State J. Med., 1952, 52, 
1029, and others). 

Albert and Gledhill {Lancet, 1944, 1, 759) 
found that absorbent dressings did not interfere 
with the action of aminacrine. 

AMINOACETIC ACID. N.F., LP. 

Glycocoll, Glycine, [Acidum Aminoaceticum] 
H2N.CH2.COOH 

"Aminoacetic Acid, dried at 105° for 2 hours, 
yields not less than 98.5 per cent and not more 
than 101.5 per cent of C2H5NO2." N.F. The LP. 
requires not less than 98.5 per cent of C2H5O2N, 
calculated with reference to the substance dried 
at 105° for 2 hours. 

Ger. Aminoessigsaure; Glykokoll; Glycin; Sp. Acido 
Aminoacetico. 

Caution. — Glycine should not be confused with 
glycin (/>-hydroxyphenyl-aminoacetic acid) , which 
is a poisonous substance. 

Aminoacetic acid, the simplest of the amino 
acids, is found in bile in combination with cholic 
acid. It is a constituent of many proteins and may 
be obtained by the hydrolysis of glue, gelatin and 
silk fibroin; Bergmann (/. Biol. Chem., 1938, 122, 
577) found that it makes up one-half of the total 
amino acids of the last-named substance. 

Several processes for preparing aminoacetic acid 
have been patented; these include hydrolysis of 
glycine esters with organic acids, alkaline hy- 
drolysis of glycine ethyl ester sulfate, hydrolysis 
of methylene-aminoacetonitrile, electrolytic re- 
duction of cyanoformic ester, as well as a method 
involving hydrolysis of neck ligaments of cattle. 
Large quantities of the acid may be conveniently 
and economically prepared, however, by the reac- 
tion of chloroacetic acid with excess ammonia at 
room temperature or with ammonium carbonate 
at a temperature of 60 to 65°. The excess of 
ammonia is evaporated and the glycine crystallized 
after addition of methyl alcohol; the product is 
purified by recrystallization from methyl alcohol- 
water solution. For other syntheses of amino- 
acetic acid see Schmidt's Chemistry of the Amino 
Acids and Proteins (Second Edition, 1944). 

While the formula of aminoacetic acid is com- 
monly written as H2N.CH2.COOH, various physi- 
cal and chemical properties of the substance in- 
dicate that it does not exist in this form. It is 
now fairly certainly established that the tendency 
of the carboxyl group to give up a proton (which 
property is characteristic of acids) and the tend- 
ency of the amino group to accept a proton 
(which property is characteristic of bases) results 



Part I 



Aminoacetic Acid 



63 



in the migration of the proton (hydrogen ion) 
from the carboxyl to the amino group, giving rise 
to a neutral ion of the composition H3+N.CH2.- 
COO~. Such an ion has been called a "zwitter- 
ion" (meaning hybrid ion) but is better called 
a "dipolar ion." The property of forming dipolar 
ions is characteristic of amino acids. Notwith- 
standing this internal neutralization of amino- 
acetic acid, the substance is capable of acting as 
an acid or a base, depending on the solvent 
medium and whether or not another base or acid 
is present to react with it. Thus, it forms a crys- 
talline salt with hydrochloric acid, aminoacetic 
acid hydrochloride, which may be used as a con- 
venient means of administering the acid since in 
the body the hydrochloric acid component is 
released. 

A suggested mechanism by which aminoacetic 
acid enters into the building-up of proteins is 
presented in the article on Amino Acids, Part II. 

Description. — "Aminoacetic Acid occurs as a 
white, odorless, crystalline powder, having a 
sweetish taste. Its solution is acid to litmus paper. 
One Gm. of Aminoacetic Acid dissolves in about 
4 ml. of water. It is very slightly soluble in alco- 
hol and in ether." N.F. 

Standards and Tests. — Identification. — (1) 
A vigorous evolution of colorless gas (nitrogen) 
results when 5 drops of diluted hydrochloric acid 
and 5 drops of a 1 in 2 solution of sodium nitrite 
are added to 5 ml. of a 1 in 10 solution of amino- 
acetic acid. (2) A deep wine color is produced 
on adding 1 ml. of ferric chloride T.S. to 2 ml. of a 

1 in 10 solution of aminoacetic acid; on adding an 
excess of diluted hydrochloric acid the color dis- 
appears, to reappear on adding stronger ammonia 
T.S. in excess. (3) A blue color is produced on 
adding 1 drop of liquefied phenol and 5 ml. of 
sodium hypochlorite T.S. to 2 ml. of a 1 in 10 
solution of aminoacetic acid. Loss on drying. — 
Not over 0.2 per cent, when dried at 105° for 

2 hours. Residue on ignition. — Not over 0.1 per 
cent. Readily carbonizable substances. — A solu- 
tion of 500 mg. of the acid in 5 ml. of sulfuric 
acid is colorless. Chloride. — The limit is 70 parts 
per million. Sulfate. — The limit is 65 parts per 
million. Heavy metals. — The limit is 20 parts per 
million. Hydrolyzable substances. — A 1 in 10 
solution of aminoacetic acid which has been boiled 
for 1 minute and then set aside for 2 hours is as 
clear and mobile as the same solution which has 
not been boiled. N.F. 

For information on the solubility of amino- 
acetic acid in mixtures of water and alcohol see 
Dunn and co-workers (/. Biol. Chem., 1938, 125, 
309). 

Assay. — About 175 mg. of aminoacetic acid, 
previously dried at 105° for 2 hours, is titrated 
with 0.1 A 7 sodium hydroxide in the presence of 
formaldehyde. Each ml. of 0.1 N sodium hy- 
droxide represents 7.507 mg. of C2H5NO2. N.F. 
For an explanation of the assay see the following 
monograph. The LP. employs the Kjeldahl method 
of assay for nitrogen. 

Incompatibilities. — The sparing solubility of 
aminoacetic acid in alcoholic liquids may cause 
its precipitation from aqueous solution on the 
addition of alcohol. Ferric salts cause a wine-red 



color, destroyed by acids; nitrites may react with 
the liberation of nitrogen. Grill (/. A. Ph. A., 
1938, 27, 871) reported development of a brown 
color in solutions of aminoacetic acid containing 
low iso-alcoholic elixir. 

Uses. — Glycine, as such, is not widely used in 
therapeutics but in combination with other phar- 
macologic agents it is important. In the metabo- 
lism of the body, aminoacetic acid is involved in 
the synthesis of body protein, creatine, glycocholic 
acid, glutathione, uric acid, heme, etc. It converts 
benzoic acid to its detoxified derivative hippuric 
acid. 

Myopathies. — The theory originally put forth 
by Thomas in 1932 that glycine was the chief 
source of the creatine of the muscles received 
support from the studies of Bloch and Schoen- 
heimer (/. Biol. Chem., 1940, 133, 633; 134, 
785), but these authors showed further that 
methionine and arginine are also converted into 
creatine (/. Biol. Chem., 1941, 138, 167). More- 
over, glycine is readily synthesized by man in 
adequate amounts (Quick, /. Biol. Chem., 1931, 
92, 65; Shemin and Rittenberg, /. Biol. Chem., 
1944, 153, 401) and it is not an essential amino 
acid in the diet (Rose, Physiol. Rev., 1938, 18, 
109). In normal men creatine does not appear in 
the urine except after violent muscular exertion, 
being excreted as a related compound creatinine. 
In certain diseases of the voluntary muscles, how- 
ever — notably so-called progressive muscular dys- 
trophy — creatine does appear in the urine. Thomas 
in 1932 tried glycine in this tragic disease. Since 
then a number of clinicians reported favorably on 
its effects, not only in progressive muscular dys- 
trophy but also in myasthenia gravis (Boothby, 
Proc. Mayo, 1932, 7, 447), poliomyelitis and 
Addison's disease, but others failed to see any 
marked benefit from the drug (J.A.M.A., 1939, 
113, 559; and 1942, 119, 1506; 1951, 147, 1185). 
Chaikelis (Am. J. Physiol., 1941, 133, 578) re- 
ported that in normal men it increases muscular 
power and delays appearance of muscle fatigue. 
Maison, however (J. A.M. A., 1940, 115, 1439), 
believes that the reported experiments dealing 
with fatigue are open to criticism. In a well- 
controlled study (J.A.M.A., 1942, 118, 594) 
glycine failed to increase the work capacity of 
human subjects. A high-protein diet seems prefer- 
able to this unessential amino acid and also to 
the incomplete protein, gelatin, which has been 
employed as a dietary source of glycine (about 
25 per cent). 

Tracer Studies. — The ready incorporation of 
glycine into so many essential compounds in the 
body has made this amino acid, when labeled with 
the isotope C 14 (Rittenberg and Shemin, J. Biol. 
Chem., 1950, 185, 103; Barnet and Wick, ibid., 
657) or N 15 (Shemin and Rittenberg, ibid., 1945, 
159, 567), most useful in the study of the inter- 
mediary metabolism of tissue and serum protein, 
hemoglobin, carbohydrate and other substances. 
Rapid incorporation into serum and tissue pro- 
tein has been observed. Only a small portion, 
varying with the nutritional status and the pro- 
tein intake, appears in the urine during the first 
24 hours. Some of the carbon is excreted as 
carbon dioxide by the lungs (Berlin et al., J. Clin. 



64 



Aminoacetic Acid 



Part I 



Inv., 1951, 30, 73). Labeled glycine has been 
employed to study the life-span of erythrocytes 
in circulating blood; the estimate of about 4 
months made with immunological methods was 
confirmed. Tracer studies show also that glycine 
is converted to uric acid (Benedict et al., Me- 
tabolism, 1952, 1, 3), creatinine (Shemin and 
Rittenberg, /. Biol. Chem., 1947, 167, 875) and 
other compounds. Since nitrogen excretion is in- 
creased by the administration of cortisone, feeding 
experiments with glycine labeled with N 15 were 
conducted by Clark (/. Biol. Chem., 1953, 200, 
69) to determine the mechanism of this action; 
the procedure used by Sprinnan and Rittenberg 
(ibid., 1949, 180, 715) was used. It was found 
that the increased nitrogen excretion during corti- 
sone therapy resulted from interference with 
protein synthesis in the tissues, with some ac- 
cumulation of amino acids in the liver. Studies 
with glycine labeled with both C 14 and N 15 have 
been conducted (Chao et al., Fed. Proc, 1952, 
11, 437). Isotope-labeled glycine has been em- 
ployed to study the effect of steroid hormones on 
the metabolism of the cells of the rat uterus. 

Peripheral Vascular Insufficiency. — Gly- 
cine possesses the metabolism-stimulating action 
of protein (so-called Specific Dynamic Action) 
which amounts to about 10 per cent of the basal 
metabolic rate). Since this heat is dissipated by 
an increase in peripheral blood flow, Gubner et al. 
(Am. J. Med. Sc, 1947, 213, 46) and Gustafson 
et al. (Surgery, 1949, 25, 539) prescribed 20 Gm. 
of glycine dissolved in 200 ml. of water by 
mouth three times daily as a vasodilator in cases 
of thromboangiitis obliterans, Raynaud's phe- 
nomenon, arteriosclerosis and other occlusive 
peripheral vascular diseases; beneficial results 
were obtained. The increase in peripheral blood 
flow was greater than that obtainable with in- 
gestion of ethyl alcohol. Collentine (/. Lab. Clin. 
Med., 1948, 33, 1555) reported on the safety of 
the intravenous administration of a 5 or 10 per 
cent solution in isotonic sodium chloride solution 
in a dose of 200 mg. per kilogram of body weight 
in a period of 30 minutes. With double this dose, 
warmth and tingling of the extremities, increased 
salivation, nausea and lightheadedness were ex- 
perienced for about 30 minutes following com- 
pletion of the injection. In two cases of cirrhosis 
of the liver, a maximum concentration of 32 mg. 
per 100 ml. of blood (method of Christensen 
et al, J. Biol. Chem., 1947, 168, 191) was found 
at the end of the injection from an initial con- 
centration of about 3 mg. per 100 ml.; the maxi- 
mum urinary excretion occurred during the half 
hour of the injection and the half hour afterward, 
and the concentration in the blood returned al- 
most to the initial level in 2>y 2 hours. 

Antacid. — A mixture of 30 per cent amino- 
acetic acid and 70 per cent calcium carbonate 
(Titralac, N.N.R., Schenley) produces an acid 
neutralization curve similar to that of whole milk 
(J.A.M.A., 1950, 152, 991); absence of systemic 
alkalosis and acid "rebound" is claimed and the 
product is recommended particularly for patients 
with peptic ulcers who are unable to tolerate milk. 
The dose is 1 to 2 tablets, each containing 150 mg. 
glycine and 350 mg. calcium carbonate, taken 



with water after meals or, in more severe cases, 
every hour. 

Dihydroxyaluminum Aminoacetate N.F. is a 
basic aluminum salt of this amino acid which is 
employed as an antacid. Its properties and uses 
are described elsewhere in Part I. 

Other Uses and Combinations. — Because of 
the amphoteric nature of aminoacetic acid it may 
be prepared in the form of aminoacetic acid hy- 
drochloride, a crystalline solid, which may be used 
as a source of hydrochloric acid for treatment of 
achlorhydria gastrica. A dose of 200 mg. of amino- 
acetic acid hydrochloride yields 0.6 ml. of diluted 
hydrochloric acid, which is an average dose of the 
latter. It is of interest in this connection that 
aminoacetic acid hydrochloride contains 32.5 
per cent of HC1 as compared with 19.9 per cent 
of HC1 in glutamic acid hydrochloride, which is 
widely used as a solid dosage form of hydro- 
chloric acid. 

Glycine esters of various phenols are used as 
bactericides, fungicides, and insecticides (Smith 
and Hansen, U. S. Patent 2,289,599, July 14, 
1942). A water-soluble glycine derivative of ribo- 
flavin has been prepared (Haas, U. S. Patent 
2,398,706, April 16, 1946). A soluble, stable, and 
less irritating form of theophylline is available 
in the compound theophylline sodium glycinate 
(q.v.). Martin and Thompson (U. S. Patent 
2,376,795, May 22, 1945) used glycine to mini- 
mize untoward effects of sulfapyridine. Amino- 
acetic acid is used as an ingredient of S0rensen's 
buffer mixtures, along with hydrochloric acid or 
sodium hydroxide. 

The dose of aminoacetic acid is from 4 to 30 
Gm. (approximately 60 grains to 1 ounce), with 
the total daily dose sometimes exceeding 60 Gm. 

Storage. — Preserve "in well-closed contain- 
ers." N.F. 

AMINOACETIC ACID ELIXIR. N.F. 

Glycine Elixir, Glycocoll Elixir, [Elixir Acidi 
Aminoacetici] 

"Aminoacetic Acid Elixir contains, in each 100 
ml., not less than 12.1 Gm. and not more than 
14.2 Gm. of C2H5NO2." N.F. 

Dissolve 131.5 Gm. of aminoacetic acid in 700 
ml. of purified water, add 60 ml. of syrup and 75 
ml. of raspberry syrup, and mix well. Dissolve 
2 Gm. of benzoic acid and 0.15 Gm. of vanillin 
in 53 ml. of alcohol and 1.5 ml. of compound 
orange spirit and add this solution to that of the 
aminoacetic acid. Filter, if necessary, and add 
sufficient water to the filtrate to make 1000 ml. 
N.F. 

Assay. — Exactly 25 ml. of aminoacetic acid 
elixir is diluted to 100 ml. with water, the solu- 
tion is decolorized with activated charcoal, filtered 
and an aliquot portion of the filtrate neutralized 
with 0.1 A T sodium hydroxide, using phenolphtha- 
lein T.S. as indicator. The volume of alkali re- 
quired is noted, but is not used as a quantitative 
measure of the aminoacetic acid present because 
of the amphoteric nature of the acid resulting 
from the presence of the amino group; the alkali 
consumed is required for the neutralization of 
benzoic acid and acid in the raspberry syrup. To 
another aliquot portion of the filtrate formalde- 



Part I 



Aminophylline 65 



hyde T.S. is added, which converts the NH2.CH2.- 
COOH to the methylene-imino compound CH2:- 
N.CH2.COOH and permits titration of the car- 
boxyl group with 0.1 N sodium hydroxide, using 
phenolphthalein T.S. as indicator and titrating to 
the same color as obtained in the first titration. 
A blank titration to correct for the acidity of the 
formaldehyde is performed and the correction 
applied to the titration in which formaldehyde 
was used. The difference between the titrations — 
with and without formaldehyde, respectively — 
represents the amount of alkali required to neu- 
tralize the carboxyl group of the aminoacetic acid. 
Each ml. of 0.1 N sodium hydroxide represents 
7.507 mg. of C2H5NO2. N.F. This titration is a 
modification of S0renson's Formol Method for 
the estimation of amino acids. For further dis- 
cussion of this assay see Green, Bull. N. F. 
Comm., 1945, 13, 84. 

Alcohol Content. — From 5 to 7 per cent, by 
volume, of C2H5OH. N.F. 

The average dose of this elixir is 15 ml. (ap- 
proximately 4 fluidrachms), representing about 2 
Gm. of aminoacetic acid. 

Storage. — Preserve "in tight containers." 
N.F. 

AMINOPHYLLINE. U.S.P., B.P., LP. 

Theophylline Ethylenediamine, [Aminophyllina] 
(C7H 8 N402)2C2H4(NH2)2.2H 2 

"Aminophylline contains not less than 75 per 
cent and not more than 82 per cent of anhydrous 
theophylline (C7H8N4O2), and not less than 12.3 
per cent and not more than 13.8 per cent of 
ethylenediamine (C2H8N2)." U.S.P. The B.P. 
and LP. requirements are identical with those 
of the U.S.P. 

The B.P. states that aminophylline may be 
prepared by dissolving theophylline in ethylene- 
diamine and evaporating the solution to dryness. 
It is reported that the compound contains a mix- 
ture of two double salts, the one consisting of 
one molecule of theophylline combined with one 
molecule of ethylenediamine, the other of one 
molecule of theophylline combined with two 
molecules of ethylenediamine. 

Description. — "Aminophylline occurs as 
white or slightly yellowish granules or powder, 
possessing a slight ammoniacal odor and a bitter 
taste. Upon exposure to air it gradually loses 
ethylenediamine and absorbs carbon dioxide with 
the liberation of free theophylline. Its solutions 
are alkaline to litmus. One Gm. of Aminophylline 
dissolves in about 5 ml. of water but owing to 
hydrolysis separation of crystals of less aminated 
theophylline begins in a few minutes, these crys- 
tals dissolving on the addition of a small amount 
of ethylenediamine. When, however, 1 Gm. is 
dissolved in 25 ml. of water the solution remains 
clear. It is insoluble in alcohol and in ether." 
U.S.P. 

Standards and Tests. — Identification. — To a 
solution of 1 Gm. of aminophylline in 20 ml. of 
water add, while stirring constantly, 1 ml. of 
diluted hydrochloric acid; filter the precipitate, 
wash it with small portions of cold water, and 
dry it at 105° for 1 hour: the substance responds 



to identification tests (1) and (2) under The- 
ophylline and melts between 270° and 274°. 
Residue on ignition. — Not over 0.15 per cent. 
U.S.P. 

Assay. — For theophylline. — A sample of 
about 250 mg. of aminophylline is dissolved in 
water containing ammonia, a measured excess of 
0.1 N silver nitrate is added to precipitate silver 
theophylline. The mixture is filtered through a 
filtering crucible, the precipitate is washed with 
water, and the excess of silver ion in the filtrate 
is determined by titration with 0.1 iV ammonium 
thiocyanate in the presence of nitric acid and 
using ferric ammonium sulfate T.S. as indicator. 
Each ml. of 0.1 N silver nitrate represents 18.02 
mg. of C7H8N4O2. For ethylenediamine. — A solu- 
tion of about 500 mg. of aminophylline is titrated 
with 0.1 Af hydrochloric acid, using methyl orange 
T.S. as indicator. Each ml. of 0.1 N acid repre- 
sents 3.005 mg. of C2H8N2. U.S.P. 

The B.P. assays for theophylline by dissolving 
about 500 mg. of aminophylline in 20 ml. of 
distilled water, neutralizing the solution with 
0.5 N hydrochloric acid using bromocresol green 
indicator and saturating the solution with sodium 
chloride, then extracting the theophylline with a 
mixture of 3 volumes of chloroform and 1 volume 
of isopropyl alcohol. The solvent is evaporated, 
and the residue is dried to constant weight at 
105°. The assay for ethylenediamine is similar 
to that of the U.S.P. The LP. assays are practi- 
cally the same as those of the U.S.P. 

Incompatibilities. — Alkaline in reaction, 
aminophylline exhibits the incompatibilities of 
alkalies. When in sufficiently concentrated solu- 
tion the theophylline in this salt is precipitated 
by acids. On exposure to air it gradually absorbs 
carbon dioxide with liberation of theophylline. 
With lactose, a yellow to brown color develops 
on standing. 

Uses. — Aminophylline has the general physio- 
logical properties of theophylline. Its chief appli- 
cations in clinical medicine depend upon its modi- 
fication of blood flow, its relaxation of the 
bronchial and other smooth musculature, its diu- 
retic action and its ability to antagonize histamine. 

Action. — It has been shown by Schack and 
Waxier (/. Pharmacol., 1949, 97, 283) that the- 
ophylline is restricted to blood plasma; it does 
not penetrate the red cell membrane and is bound 
only slightly to blood proteins. Further, it appears 
to be bound only slightly to tissue proteins. They 
concluded that its therapeutic effect is closely 
related to the level in the blood. Based upon this 
finding and because there is conflicting opinion as 
to the therapeutic effectiveness of this drug, 
Waxier and Schack (J.A.M.A., 1950, 143, 736) 
studied the blood theophylline levels after admin- 
istration of various doses of aminophylline by 
the intravenous, intramuscular, oral and rectal 
routes. Following intravenous injection of 250 mg. 
of aminophylline the blood concentration falls 
progressively to approximate zero after 9 hours. 
Sustained blood levels followed intramuscular in- 
jection of 500 mg., appreciable levels persisting 
for 13 hours. They noted that this dosage given 
intramuscularly produced values about twice as 
high as a dose of 250 mg., persisted about twice 



66 Aminophylline 



Part I 



as long, and was no more painful than the smaller 
dose. Theophylline appeared in circulating blood 
within 15 minutes after ingestion of an uncoated 
tablet containing 200 mg., significant levels per- 
sisting for 9 hours. There was a delay of 2 hours 
after oral ingestion of enteric-coated tablets be- 
fore the drug was demonstrable in the blood 
plasma, significant levels persisting 7 hours after 
a dose of 200 mg. and 10 hours with a 300 mg. 
dose. Suppositories containing 500 mg. produced 
widely varying values. 

Wechsler et al. (J. Clin. Inv., 1950, 29, 28) 
studied the cerebral circulation and metabolism 
following intravenously administered aminophyl- 
line and demonstrated conclusively that it results 
in diminished cerebral blood flow due to increased 
cerebrovascular resistance. There was a drop in 
arterial carbon dioxide tension and a rise in arte- 
rial pH. They were of the opinion that aminophyl- 
line constricts the cerebral vessels, decreasing 
cerebral blood flow, increasing carbon dioxide 
tension of the brain, thus providing a stimulus 
for hyperventilation, as reflected by the rising 
pH. Moyer et al. (J. Clin. Inv., 1952, 31, 267) 
pointed out that the arrest of Cheyne-Stokes 
respiration after aminophylline cannot, therefore, 
result from an increase of cerebral blood flow, 
but is probably due either to a direct stimulating 
effect on the respiratory center or an indirect 
effect secondary to the depressed cerebral circu- 
lation and resultant rise in tissue carbon dioxide 
of the medulla. They found no difference in the 
cerebral hemodynamic response to aminophylline 
of patients in cardiac failure exhibiting Cheyne- 
Stokes respiration and those with regular respi- 
ration. 

Leroy and Speer (/. Pharmacol., 1940, 69, 45) 
found aminophylline to be twice as active as the- 
ophylline sodium in dilating the coronary vessels. 
Hanzlik and Moy (Standford M. Bull., 1945, 3, 
127), in experiments on dogs, found that intrave- 
nous aminophylline inhibits coronary constriction 
produced by posterior pituitary solution, conclud- 
ing that its effects are fundamentally vascular 
rather than a direct stimulation of the myo- 
cardium. Stewart (Cardiac Therapy, 1952 p. 27) 
states that aminophylline induces its benefit in 
pulmonary edema by increasing cardiac output, 
probably by direct action on the heart muscle, 
and by lowering the venous pressure. Escher 
et al. (Fed. Proc, 1948, 7, 31, part I) demon- 
strated that in normal human subjects rapid in- 
travenous administration of aminophylline pro- 
duced a significant increase in cardiac output 
lasting 10 to 20 minutes, paralleling a brief in- 
crease in renal plasma flow; glomerular filtration 
rate remained high for as long as one hour despite 
a fall in renal plasma flow to below control levels. 
In chronic congestive heart failure it produces a 
marked increase in cardiac output lasting as long 
as one hour. It has been demonstrated by Segal 
and associates (/. Clin. Inv., 1949, 28, 1190) that 
aminophylline given intravenously provides im- 
mediate protection against the bronchospastic ef- 
fect of intravenously administered histamine or 
methacholine. The drug is a gastric irritant and 
it has been shown by Krasnow et al. (Proc. S. 
Exp. Biol. Med., 1949, 71, 335) to stimulate 



production of free hydrochloric acid in the stom- 
ach after intravenous administration. 

Therapeutic Uses. — Aminophylline is valuable 
in treating bronchial asthma, particularly by the 
intravenous route, and is often effective in cases 
of status asthmaticus in patients who have become 
refractory to epinephrine (see Herrmann and 
Aynesworth, J. Lab. Clin. Med., 1937, 23, 135). 
It is likewise beneficial in asthmatic bronchitis 
and unresolved pneumonia. Barach (J. A.M. A., 
1945, 128, 589) has obtained relief of bronchial 
spasm within 10 to 30 minutes following rectal 
instillation of aminophylline solution. This mode 
of administration is advantageous in that it may 
be used by nurses or patients themselves. Accord- 
ing to Waldbott (I.A.M.A., 1945, 128, 1205) 
sensitivity to this drug has never been demon- 
strated. Barach also found (I.A.M.A., 1951, 147, 
730) that for palliative therapy in patients with 
bronchial asthma or the bronchospastic type of 
chronic hypertrophic pulmonary emphysema in 
the absence of status asthmaticus, aminophylline 
in doses of 200 to 300 mg. is the most satisfac- 
tory oral medication for relief of bronchospasm. 
For maximal effect it must be given when the 
stomach is empty; if nausea results it may be 
relieved by two teaspoonfuls of aluminum hy- 
droxide gel. Whitfield et al. (Lancet, 1951, 260, 
490) found it valueless in emphysema in the ab- 
sence of bronchospasm. Kugelmass (J.A.M.A., 
1951, 147, 1240) used aminophylline to relax 
the bronchial and esophageal musculature to dis- 
lodge foreign bodies inspired or swallowed by 
children, avoiding the need for endoscopy; he 
gave 250 mg. in a solution instilled rectally. 
Taplin et al. (Ann. Allergy, 1949, 7, 513) found 
that aminophylline or theophylline-lactose powder, 
in particle sizes of 0.5 to 5 n in diameter, when 
given by inhalation in a dosage of 60 mg., will 
relieve bronchial spasm in a majority of patients 
almost immediately, but for a somewhat shorter 
period than with intravenous administration. They 
noted no systemic vasomotor, allergic or local 
irritative effects. 

The vasodilator action of aminophylline is 
recommended in recent myocardial infarction by 
Mikotoff and Katz (Am. Heart J., 1945, 30, 215). 
Bakst et al. (ibid., 1948, 36, 527) found that 
intravenous injection of 240 mg. of aminophyl- 
line increases the capacity for effort without pain 
in patients with angina of effort. It is widely 
used in patients with coronary artery disease 
in doses of 100 to 200 mg. 3 or 4 times daily by 
mouth. Russek et al. (J.A.M.A., 1953, 153, 207) 
compared the ability of various drugs to modify 
the electrocardiographic response to standard exer- 
cise (Master two-step test) in carefully selected 
patients with coronary artery disease. They found 
that aminophylline in doses of 500 mg. adminis- 
tered intravenously or 400 mg. by the oral route 
produced only a slight or insignificant effect. Its 
use is recommended in treatment of pulmonary 
edema, 250 or 500 mg. being injected by vein. 
Similar amounts are used at bedtime to prevent 
occurrence of nocturnal dyspnea. Suppositories 
containing 500 mg. may be substituted for this 
purpose. Kissin et al. (Angiology, 1951, 2, 217) 
found an average improvement in exercise toler- 



Part I 



Aminophylline 67 



ance of 42 per cent in subjects with intermittent 
claudication due to obliterating arteriosclerosis, 
following intravenous administration of a dose 
of 240 mg. Rickles (/. Florida M. Assn., 1951, 
38, 263) obtained relief of arterial spasm in simi- 
lar cases by direct injection of aminophylline into 
the femoral artery, with no untoward results. 
Mover and associates (Am. J. Med. Sc, 1952, 
224, 377) found the drug useful in relieving 
hypertensive headaches, the dosage being 500 
mg. intravenously. Mainzer (Schweiz. med. 
Wchnschr., 1949, 79, 108) found intravenous 
doses of 240 mg. to be of benefit in treatment 
of cerebral hemorrhage. 

Aminophylline was the only injectable diuretic 
preparation prior to the introduction of the 
organic mercurials. Vogl and Esserman {J. A.M. A., 
1951, 147, 625) called attention to the fact that 
in addition to increasing the effective renal blood 
flow and glomerular filtration rate it inhibits 
renal tubular reabsorption, the latter being largely 
responsible for its diuretic effect. Unlike the or- 
ganic mercurial diuretics, however, it does not 
produce demonstrable damage to the tubular 
epithelium. They evolved a schedule using a mer- 
curial injection intermittently every third day, 
with multiple daily aminophylline injections to 
potentiate and maintain diuresis in patients with 
advanced congestive heart failure who are ap- 
parently refractory to mercurial diuretics. 

Cole (Am. J. Surg., 1946, 72, 719) reported 
that intravenous administration of 500 mg. of 
aminophylline produced in 9 out of 10 patients 
relief from biliary colic within 5 to 7 minutes. 
Seneque et al. (J. de Chirurgie, 1952, 68, 340) 
found that it facilitates passage of residual biliary 
calculi from the common bile duct following 
biliary surgery and in conjunction with Pribam's 
method of stimulating the flow of bile. Anderson 
and Mclntyre (Nebr. State M. J., 1949, 34, 17) 
found oral aminophylline useful in treating pri- 
mary dysmenorrhea. Epstein (Arch. Dermat. 
Syph., 1948, 58, 47) observed aminophylline, in- 
travenously administered in a dose of 500 mg. 
in 20 ml. of diluent, to give immediate relief in 
patients with acute pruritic dermatoses. 

Summary. — Aminophylline is used in treat- 
ment of bronchial asthma and other bronchospas- 
tic conditions, cardiac asthma and pulmonary 
edema, coronary artery disease, obliterating arte- 
riosclerosis, hypertensive headache and cerebral 
hemorrhage, as a diuretic in congestive cardiac 
failure either alone or to potentiate the effect of 
mercurial diuretics, in biliary colic and in various 
acute pruritic dermatoses. lYJ 

Comparison of Routes of Administration. 
— Rectal instillation of an aqueous solution of 
aminophylline results in almost as rapid absorp- 
tion as does intravenous injection (Barach, Bull. 
N. Y. Acad. Med., 1944, 20, 538) ; rectal adminis- 
tration avoids the infrequent but serious instances 
of vascular collapse or fatal cardiac response 
which may follow intravenous administration. Ab- 
sorption from rectal suppositories is uncertain, 
occasionally producing blood theophylline levels 
comparable to those obtained by intravenous in- 
jection of the same dose of aminophylline but 
generally yielding low levels. Prigal et al. (J. Al- 



lergy, 1946, 17, 172) found suppositories con- 
taining aminophylline and pentobarbital sodium 
to relieve asthma in about half the time required 
for aminophylline alone. Oral administration of 
aminophylline is less effective than when the 
drug is given by the intravenous route or when 
it is instilled rectally as an aqueous solution, 
principally because the majority of patients de- 
velop gastrointestinal disturbances after pro- 
longed use. Enteric-coated tablets have been em- 
ployed to overcome this disadvantage and, re- 
cently, it has been observed that simultaneous 
administration of aluminum hydroxide decreases 
the incidence of gastrointestinal disturbances in 
most patients to such a degree that sufficient 
aminophylline may be given orally to produce 
levels of theophylline in the blood which are 
comparable to those obtained by intravenous ad- 
ministration (Cronheim et. al., Postgrad. Med., 
1953, 13, 432); the aluminum hydroxide appears 
not to alter the rate or the degree of absorption 
of aminophylline, as compared with tablets of 
aminophylline by itself. 

Toxicology. — Scherf and Schlachman (Am. 
J. Med. Sc, 1946, 212, 83) observed diminished 
prothrombin time in patients to whom aminophyl- 
line was administered intravenously. It has been 
believed that this effect, shared by other methyl- 
xanthines, may augment the risk of thrombosis 
in certain patients receiving aminophylline or 
kindred drugs. However, studies by Blood and 
Patterson (Proc. S. Exp. Biol. Med., 1948, 69, 
130) and by Holland and Gross (/. Iowa M. Soc, 
38, 183) indicate that oral or intravenous admin- 
istration of aminophylline produces no statisti- 
cally significant changes in clotting time or plasma 
prothrombin time. Studies by Overman and 
Wright (Am. Heart J., 1950, 39, 65) of the ef- 
fects of oral ingestion of the drug led them to 
the same conclusion. 

Intravenous injections must be given very 
slowly, minimum time being 4 to 5 minutes, and 
the solution should be warmed to body tempera- 
ture before use. Rapid administration may lead 
to peripheral vascular collapse. In at least 6 re- 
ported instances (see Bresnick et al., J.A.M.A., 
1948, 136, 397) sudden death has followed in- 
travenous administration. In each instance there 
was evidence of myocardial disease and the sud- 
denness of death suggested the probability that 
cardiac standstill or ventricular fibrillation had 
occurred. Excessive cerebral stimulation may re- 
sult in wakefulness, vertigo, vomiting, hyperpnea 
and even generalized convulsions. 

Dose. — The usual oral dose of aminophylline 
is 200 mg. (approximately 3 grains) 3 times daily, 
with a range of 100 to 200 mg.; the maximum 
safe dose is 200 mg. and the total dose in 24 
hours should generally not exceed 600 mg. When 
aluminum hydroxide is given simultaneously 
larger doses of aminophylline may be tolerated; 
Cronheim et al. (loc. cit.) found most of their 
patients to tolerate doses of 1 to 1.6 Gm. (15 to 
24 grains), which produced a reliable diuretic 
effect, and some as much as 2.4 Gm. (36 grains) 
of aminophylline per day when thus adminis- 
tered. Per rectum, the usual dose is 500 mg. 
(approximately lYz grains) 1 or 2 times daily, 



68 Aminophylline 



Part I 



with a range of 250 to 500 mg.; the maximum 
safe dose is 500 mg. and the total dose in 24 
hours should not exceed 1 Gm. By intravenous 
injection, the usual dose is 500 mg. (approxi- 
mately l x /z grains) up to 3 times daily, with a 
range of 250 to 500 mg.; the maximum safe dose 
is 500 mg. and the total dose in 24 hours should 
not exceed 1.5 Gm. 

Storage. — Preserve "in tight containers." 
U.S.P. 

AMINOPHYLLINE INJECTION. 
U.S.P. (B.P., LP.) 

[Injectio Aminophyllinae] 

"Aminophylline Injection is a sterile solution 
of aminophylline in water for injection. It con- 
tains not less than 93 per cent and not more 
than 107 per cent of the labeled amount of 
C16H24N10O4.2H2O. For the purpose of stabiliza- 
tion, Aminophylline Injection may contain added 
freshly distilled ethylenediamine solution amount- 
ing to not more than 60 mg. of C2H8N2 for each 
1 Gm. of aminophylline." U.S.P. 

The B.P. defines Injection of Aminophylline as 
a sterile solution of aminophylline in water for 
injection free from carbon dioxide; ethylenedia- 
mine may be added to aid solution, provided the 
pH of the solution does not exceed 9.6. The solu- 
tion is directed to be sterilized by heating in an 
autoclave, or by filtration through a bacteria- 
proof filter. The content of anhydrous theophyl- 
line is not less than 71.0 per cent and not more 
than 86.0 per cent of the labeled content of 
aminophylline. The LP. limits for anhydrous 
theophylline are 73.0 and 83.0 per cent, respec- 
tively; for ethylenediamine (C2H8X2) the limits 
are 12.3 and 19.8 per cent, respectively. 

B.P. Injection of Aminophylline; Injectio Theophyl- 
linae cum .SSthylenediamina. LP. Injection of Amino- 
phylline; Injectio Aminophyllini. Sp. Inyeccion de 
Aminofilina. 

The U.S.P. permits an inordinate excess of 
ethylenediamine (43 per cent above the upper 
limit provided under Aminophylline) to be used 
"for the purpose of stabilization." If the amino- 
phylline and the injection are carefully prepared 
so as to prevent absorption of carbon dioxide, 
even the most concentrated injection employed 
clinically may be made with at most only a frac- 
tion of the permitted excess of ethylenediamine. 

For uses and dose see under Aminophylline. 

Storage. — Preserve "in single-dose contain- 
ers, preferably of Type I glass." U.S.P. 

Usual Sizes. — 2 ml. containing 500 mg. (ap- 
proximately 7^2 grains) for intramuscular use; 
10 ml. or 20 ml. containing respectively 250 mg. 
or 500 mg. (approximately 4 or 7^ grains) for 
intravenous use. 

AMINOPHYLLINE SUPPOSITORIES. 
U.S.P. 

[Suppositoria Aminophyllinae] 

"Aminophylline Suppositories contain not less 
than 90 per cent and not more than 110 per cent 
of the labeled amount of C16H24X10O4.2H2O." 
U.S.P. 

While the U.S.P. does not specify the supposi- 



tory base which may be employed, a number of 
the products on the market are stated to be made 
with a Carbowax base; one such base may be 
prepared by melting together 1 part of Carbowax 
4000 (polyethylene glycol 4000, U.S.P. XV) 
and 2 to 3 parts of Carbowax 1540. Such a base 
will not melt at body temperature but will gradu- 
ally release dispersed medication when sufficient 
moisture is absorbed by the suppository, following 
insertion in the rectum, to dissolve the base. 

For uses and dose see under Aminophylline. 

Storage. — Preserve "in well-closed containers 
in a cold place." U.S.P. 

Usual Size. — 500 mg. (approximately l 1 /* 
grains) of aminophylline. 

AMINOPHYLLINE TABLETS. 
U.S.P. (B.P., LP.) 

[Tabellae Aminophyllinae] 

"Aminophylline Tablets contain not less than 
93 per cent and not more than 107 per cent of 
the labeled amount of C16H24X10O4.2H2O." 
U.S.P. The B.P. requires the content of anhy- 
drous theophylline to be not less than 67.5 per 
cent and not more than 86.0 per cent, and the 
content of ethylenediamine to be not less than 
11.1 per cent and not more than 15.2 per cent, of 
the labeled amount of aminophylline. The LP. 
requires not less than 73.0 per cent and not more 
than 84.0 per cent of anhydrous theophylline. 

B.P. Tablets of Aminophylline; Tabellae Theophyllinae 
cum iEthylenediamina. LP. Compressi Aminophyllini. 
Sp. Tablet as de Aminofilina. 

Storage. — Preserve "in tight containers." 
U.S.P. 

Usual Sizes. — 100 and 200 mg. (approxi- 
mately \y 2 and 3 grains), enteric coated tablets 
or tablets containing aluminum hydroxide being 
generally preferred to avoid gastric irritation. 
Tablets containing aminophylline and phenobar- 
bital are frequently prescribed. 

AMINOPYRINE. X.F. (LP.) 

Amidopyrine, [Aminopyrina] 



CH, 



./ 



CH, 



lX3 



(CH 3 ) 2 N X 

The LP. defines Amidopyrine as 2 :3-dimethyl- 
4-dimethylamino-l -phenyl- 5-pyrazoIone. 

LP. Amidopyrine, Amidopyrinum. Pyramidon (.Win- 
throp), Dimethylamino Antipyrine. Fr. Dimethylamino- 
phenyldimethylpyrazolone. C-er. Dimethylamino-phenyldi- 
methylpyrazolon. It. Fenil-dimetil-dimetilamido-isopira- 
zolone. Sp. Aminoantipirina ; Aminopirina; Amidopirina. 

This compound, first prepared in 1893, may be 
regarded as a derivative of antipyrine in which a 
hydrogen atom of the pyrazolone group is re- 
placed by a dimethylamino or N(CHs)2 group. 
It is designated as 1.5-dimethyl-4-dimethylamino- 
2-phenyl-3-pyrazolone according to the standard 
United States nomenclature. Aminopyrine is 
manufactured by the reduction of isonitrosoanti- 
pyrine with zinc and subsequent methylation of 



Part I 



Aminopyrine Elixir 69 



the resulting 4-amino-antipyrine by means of 
methyl iodide or dimethyl sulfate. Because of the 
difficulty of directly methylating the aminoanti- 
pyrine various means of indirectly accomplishing 
this have been employed. 

Description. — "Aminopyrine occurs as color- 
less or white, small crystals, or as a white, crystal- 
line powder. It is odorless and is stable in air 
but is affected by light. Its solutions are alkaline 
to litmus paper. One Gm. of Aminopyrine dis- 
solves in 18 ml. of water, in 1.5 ml. of alcohol, 
in 1 ml. of chloroform, and in 13 ml. of ether. 
Aminopyrine melts between 106.5° and 109°." 
N.F. 

Standards and Tests. — Identification. — (1) 
A bluish violet color develops on adding 3 drops 
of diluted hydrochloric acid and 1 ml. of ferric 
chloride T.S. to 5 ml. of a 1 in 25 solution of 
aminopyrine; the color changes to violet red on 
adding a few drops of diluted sulfuric acid. (2) 
A deep violet color, changing to a grayish black 
precipitate of silver, is formed on adding 5 drops 
of silver nitrate T.S. to 5 ml. of a 1 in 25 solu- 
tion of aminopyrine. (3) A dark blue color or 
precipitate is immediately formed when a 1 in 25 
solution of aminopyrine is added to a freshly pre- 
pared potassium ferricyanide T.S. containing 
some ferric chloride (difference from antipyrine). 
Loss on drying. — Not over 1 per cent, when dried 
at 60° for 2 hours. Residue on ignition. — Not 
over 0. 1 5 per cent. Chloride. — A purple color, but 
no turbidity, is immediately produced on adding 
silver nitrate T.S. to a solution of aminopyrine 
acidified with nitric acid. Heavy metals. — The 
limit is 20 parts per million. Readily carbonizable 
substances. — A solution of 100 mg. of aminopy- 
rine in 1 ml. of sulfuric acid is colorless. Anti- 
pyrine. — A mixture of 100 mg. of aminopyrine, 
100 mg. vanillin, 5 ml. of water and 2 ml. of 
sulfuric acid, heated to boiling, has no more 
color than a mixture of 5 ml. of water, 2 ml. of 
sulfuric acid, and 100 mg. of vanillin, also heated 
to boiling. N.F. 

Incompatibilities. — Aminopyrine has incom- 
patibilities very similar to those of antipyrine. It 
is precipitated by many alkaloidal reagents includ- 
ing iodine, tannic acid and Mayer's reagent. 
Oxidizing agents produce a blue to violet color; 
these include ferric chloride, silver nitrate, nitric 
acid, nitrites, iodine, and certain enzymes. Calo- 
mel and mercury bichloride are reduced. Aspirin 
and salol are discolored and become moist when 
mixed with it, as do citric, tartaric, and salicylic 
acids, phenol, and chloral hydrate. Solutions of 
aminopyrine when mixed with acacia show a color 
change from violet, through yellow to brown. 
This is due to the oxidase of acacia and may be 
prevented by previously heating the mucilage on 
a water bath for 30 minutes. 

Uses. — Aminopyrine is one of the most power- 
ful analgesics of the "coal-tar group" but because 
of its frequent incrimination in cases of agranulo- 
cytosis its use in this country has been largely 
discontinued. Its effect on the threshold for pain, 
produced by radiant heat on the normal skin, was 
no different than that of the equivalent dose of 
acetanilid or acetylsalicylic acid (Wolff, Hardy 
and Goodell, /. Clin. Inv., 1941, 20, 63). It 



will relieve neuralgic headaches, dysmenorrhea, 
rheumatism and similar painful conditions. In 
rheumatic fever it causes diminution of fever 
and relieves the joint pain as effectively as do 
the salicylates; small doses, such as 300 mg. 
three to six times daily, are adequate (McEwen, 
Bull. N. Y. Acad. Med., 1943, 19, 679). A few 
authors believe it has a specific curative effect on 
the progress of the disease. (Bodenstab, Deutsches 
Arch. klin. Med., 1928, 159, 129). Contrary to 
some reports Borafski and Steigmann (J.A.M.A., 
1933, 100, 1859) found its effects in measles to 
be not essentially different from those of other 
coal-tar antipyretics. In 1932 Scherf reported 
symptomatic relief in diabetes insipidus; this was 
confirmed by Kahn (J.A.M.A., 1933, 100, 1593). 
Large doses of the drug intravenously will cause 
a great reduction in the output of urine for 6 or 8 
hours, but when used repeatedly it loses its anti- 
diuretic power. In healthy persons Weitzman 
(Ztschr. klin. Med., 1940, 137, 429) reported 
that it caused increased rather than decreased 
diuresis following the ingestion of a large amount 
of water. 

Toxicology. — The most dangerous outcome 
from the use of aminopyrine is the agranulocy- 
tosis which develops in some patients; this con- 
sists of a very low leukocyte count in the blood 
(as low as a few hundred per cu. mm.), an almost 
total absence of granulocytes (neutrophils), a 
maturation arrest of myeloblasts in the bone mar- 
row, fever, malaise, necrotic ulcerations of the 
throat and other mucous membranes, prostration 
and death in as high as 70 per cent of cases 
(Kracke and Parker, J. A.M. A., 1938, 111, 1255, 
and FitzHugh, ibid., p. 1643). Since agranulocy- 
tosis is so often fatal, and since other effective 
analgesic drugs are available, the use of amino- 
pyrine has been largely discontinued, [v] 

The analgesic dose of aminopyrine is from 130 
to 300 mg. (approximately 2 to 5 grains) ; a 
maximum single dose of 600 mg. and maximum 
total doses of 1 to 3 Gm. in a period of 24 hours 
are recorded, which latter dose is hardly to be 
considered safe. 

Storage. — Preserve "in well-closed, light- 
resistant containers." N.F. 



AMINOPYRINE ELIXIR. N.F. 

Amidopyrine Elixir, [Elixir Aminopyrinae] 

"Aminopyrine Elixir contains, in each 100 ml., 
not less than 3.7 Gm. and not more than 4.3 Gm. 
of C13H17N3O." N.F. 

Dissolve 40 Gm. of aminopyrine in 200 ml. of 
alcohol, add 3 ml. of compound orange spirit, 10 
ml. of compound amaranth solution, 60 ml. of 
glycerin, 400 ml. of syrup, and enough purified 
water to make the product measure 1000 ml. Mix 
well and filter, if necessary, to produce a clear 
liquid. N.F. 

Assay. — A sample of 5 ml. of elixir is alka- 
linized with ammonia and the aminopyrine ex- 
tracted with successive portions of chloroform. 
After washing the chloroform solution with water, 
the former is filtered into a tared beaker, the 
solvent is evaporated and the residue of amino- 



70 



Aminopyrine Elixir 



Part I 



pyrine dried at 60° for 2 hours, cooled, and 
weighed. N.F. 

Alcohol Content. — From 17 to 20 per cent, 
by volume, of C2H5OH. N.F. 

This preparation is an acceptable dosage form 
for aminopyrine, but it should be used cautiously 
in view of the potential harmful effect of the 
active ingredient. The N.F. gives the usual dose 
as 4 ml. (approximately 1 fluidrachm). which 
represents about 160 mg. (approximately 2y 2 
grains) of aminopyrine. 

Storage. — Preserve "in tight containers." N.F. 

AMINOPYRINE TABLETS. X.F. (LP.) 

Amidopyrine Tablets, [Tabellae Aminopyrinae] 

"Aminopyrine Tablets contain not less than 94 
per cent and not more than 106 per cent of the 
labeled amount of C13H17N3O." N.F. The LP. 
limits are 93.0 and 107.0 per cent, respectively. 

I. P. Tablets of Amidopyrine; Compressi Amidopyrini. 

Assay. — A representative sample of tablets, 
equivalent to 1 Gm. of aminopyrine. is dissolved 
in 1 N hydrochloric acid. After filtering to re- 
move insoluble matter an aliquot portion of the 
filtrate is rendered alkaline with ammonia T.S. 
and the aminopyrine extracted with chloroform. 
The chloroform is evaporated and the residue of 
aminopyrine dried at 60° for 2 hours, cooled and 
weighed. N.F. 

Usual Size. — 5 grains (approximately 300 
mg.). 

AMINOSALICYLIC ACID. U.S.P., (LP.) 

Para-aminosalicylic Acid, PAS 



COOH 




"Aminosalicylic Acid contains not less than 
98.5 per cent of C7H7NO3. calculated on the dried 
basis." U.S.P. The LP. requires not less than 97.0 
per cent of the active component, referred to the 
substance as it is found. 

"Caution. — Prepare solutions of Aminosalicylic 
Acid within 24 hours of administration. Under no 
circumstances use a solution if its color is darker 
than that of a freshly prepared solution." U.S.P. 

LP. Para-aminosalicylic Acid; Acidum Para-amino- 
salicylicum. Pamisyl {Parke-Davis). 4-Aminosalicylic Acid; 
4-Amino-2-hydroxybenzoic Acid. 

This tuberculostatic agent may be synthesized 
by several processes, as by carboxylation of m- 
aminophenol, reduction of />-nitrosalicylic acid, 
or by a 4-step synthesis starting with 4-nitro-2- 
aminotoluene (J.A.Ph.A., 1949, 38, 9). Besides 
the acid, the calcium and sodium salts are official. 

Description. — "Aminosalicylic Acid is a white 
or nearly white, bulky powder, darkening on 
exposure to fight and air. It is odorless or has a 
slight acetous odor. One Gm. of Aminosalicylic 
Acid dissolves in about 500 ml. of water and in 
about 21 ml. of alcohol. It is slightly soluble in 
ether and practically insoluble in benzene." U.S.P. 

Standards and Tests. — Identification. — (1) 
.The diacetyl derivative melts at about 191°. (2) 



On adding ferric chloride T.S. to a saturated solu- 
tion a violet color is produced. (3) The acid 
melts rapidly, with evolution of carbon dioxide, 
between 145° and 150°. pH — The pH of a satu- 
rated solution is between 3.0 and 3.7. Water. — 
Not over 0.5 per cent, when determined by the 
Karl Fischer method. Residue on ignition. — Not 
over 0.1 per cent. Clarity and color of solution. — 
1 Gm. dissolves in 10 ml. of 1 in 10 sodium bicar- 
bonate solution to give a clear solution which has 
no more than a faint yellow color. Chloride. — 
The limit is 140 parts per million. Arsenic. — The 
limit is 10 parts per million. Heavy metals. — The 
limit is 30 parts per million, m- Amino phenol. — 
Not over 0.2 per cent. U.S.P. 

Assay. — About 300 mg. of aminosalicylic acid 
is dissolved in glacial acetic acid, after which cold 
water, ice, and hydrochloric acid are added and 
the solution is titrated with 0.1 M sodium nitrite 
until it produces with starch iodide paste a blue 
color immediately. In this assay the amino group 
is quantitatively diazotized. with one molecule of 
aminosalicylic acid reacting with one molecule of 
sodium nitrite. Each ml. of 0.1 M sodium nitrite 
represents 15.31 mg. of C7H7NO3. U.S.P. In the 
LP. assay about 300 mg. of the acid is dissolved 
in 5 ml. of acetone and titrated with 0.1 A7 sodium 
hydroxide, using bromothymol blue as indicator. 
Each ml. of 0.1 N sodium hvdroxide represents 
15.31 mg. of C7H7NO3. 

Stability. — Oberweger et al. {Quart. J. P., 
194S, 21, 292) investigated the stability of both 
the acid and its sodium salt. Dry aminosalicylic 
acid evolves carbon dioxide at temperatures above 
100° C, melting during the decomposition; the 
sodium salt is quite stable even when heated at 
150° C. for an hour and may be sterilized in the 
dry state by this procedure, after first dehydrating 
the dihydrate at 100° to 110° for 1.5 hour's. Aque- 
ous solutions of the acid are relatively unstable, 
particularly at elevated temperatures; the acid 
decomposes to w-aminophenol. with liberation of 
carbon dioxide. Explosions due to the accumulated 
pressure of the gas formed in acid solutions of 
aminosalicylic acid have been reported (Bulletin 
of the American Society of Hospital Pharmacists, 
Jan. -Feb., 1950, page 21). The sodium salt is con- 
siderably more stable in aqueous solution and can 
be boiled without marked decarboxylation; steri- 
lization by autoclaving results in appreciable de- 
composition (15 per cent in a 1 to 5 solution 
according to Oberweger et al.). Solutions of the 
sodium salt develop a yellow to brown color; 
color formation may be delayed if not avoided 
entirely by dissolving 0.1 per cent of sodium 
metabisulfite in the solution. Solutions of the so- 
dium salt for oral use may be prepared from 
anhydrous aminosalicylic acid by the reaction, in 
water, of 153 parts of the acid with 84 parts of 
sodium bicarbonate, i.e., in the proportion of the 
molecular weights of the two substances. 

Uses. — Aminosalicylic acid has been used in 
the treatment of human tuberculosis since Leh- 
mann's observation (Lancet, 1946, 250, 15) that 
it possesses bacteriostatic activity against tubercle 
bacilli. 

Action. — The acid is rapidly absorbed from 
the gastrointestinal tract and diffuses generally 



Part I 



Ammonia 



71 



throughout the tissues, the highest concentrations 
being found in the kidney, lung and liver; it is 
also found in cerebrospinal fluid. While a concen- 
tration of 0.15 mg. per 100 ml. is bacteriostatic 
when tested against tubercle bacilli, in vitro (Leh- 
mann, loc. cit.), the blood levels when thera- 
peutic doses are given are of the order of 2 to 11 
mg. per 100 ml. and even higher. Aminosalicylic 
acid must be given at intervals of 2.5 to 3 hours 
to maintain continuously elevated blood levels. 
Almost all of it is excreted in the urine within 
10 hours (McClosky et al, J. Pharmacol., 1948, 
92, 447; Way et al, ibid., 1948, 93, 368; Venka- 
taraman et al, J. Biol. Chem., 1948, 173, 641). 
The acid is bacteriostatic rather than bactericidal 
but the exact metabolic function altered to inhibit 
growth is undetermined. 

Tuberculosis. — Bogen (Am. Rev. Tuberc, 
1950, 61, 226), in an extensively annotated re- 
view, reported that most investigators found early 
marked symptomatic improvement, with less 
cough and sputum, increased appetite, slowing of 
pulse and respiration, and a drop in temperature 
especially in fever due to tuberculous pneumonia 
or pleurisy, following use of aminosalicylic acid. 
When used alone, however, the acid has proved 
to be less effective than streptomycin (Tempel, 
J.A.M.A., 1952, 150, 1165). Aminosalicylic acid 
may be given by itself in the treatment of infec- 
tions due to streptomycin-resistant tubercle ba- 
cilli (American Trudeau Society, Am. Rev. 
Tuberc, 1951, 63, 617). Its use in conjunction 
with isonicotinic acid hydrazide is being investi- 
gated (Trans. 12th Conf. Chemoth. Tbc, 1953). 
Some authorities recommend aminosalicylic acid 
alone during the long-range preparation of pa- 
tients for resectional operation. Others use it for 
symptomatic relief of protracted, incurable tuber- 
culosis. 

The concomitant administration of aminosali- 
cylic acid and streptomycin markedly delays the 
emergence of streptomycin-resistant strains of 
tubercle bacilli and thus prolongs the therapeutic 
effect of the antibiotic. On a 120-day regimen of 
12 Gm. of aminosalicylic acid daily and 1 Gm. of 
streptomycin twice a week, resistance to 10 micro- 
grams per ml. of the latter was reduced from 82 
per cent to less than 20 per cent (Report, Council 
on Pharm. & Chem., J.A.M.A., 1951, 147, 253). 
This significant reduction in bacterial resistance 
has been accomplished without any sacrifice in 
therapeutic efficacy. In fact, pulmonary, miliary, 
meningeal, and other forms of tuberculosis have 
all shown clinical improvement on the combined 
regimen. 

Toxicology. — Gastrointestinal disturbances, 
consisting of nausea, vomiting, and diarrhea, are 
rather frequent early in the course of treatment 
but may subside with continued therapy. Reduc- 
tion in gastrointestinal irritation has been re- 
ported to be obtained by use of enteric-coated 
tablets or granules, by dispersion in a flavored 
effervescent drink, by oral or intravenous adminis- 
tration of a solution of the sodium salt or by 
oral use of the potassium salt in solution. Serious 
toxic reactions are rare. A few allergic reactions, 
including dermatitis and drug fever, have been 
reported. Muri (Nor disk Med., 1952, 47, 141) 



reported a case of fatal aminosalicylic acid intoxi- 
cation and Steininger et al. (Am. Rev. Tuberc, 
1954, 69, 451) reported a fatal allergic reaction 
from a 5.5-Gm. dose of sodium aminosalicylate. 
Several reports of thyroid enlargement occurring 
during therapy with aminosalicylic acid have ap- 
peared (Brinkman and Coates, ibid., 1954, 69, 
458). Purpura and a mild hypoprothrombinemia 
have been observed. Patients with impaired he- 
patic or renal function should be given aminosali- 
cylic acid with caution. 

Dose. — The usual dose is 3 Gm. (approxi- 
mately 45 grains) 4 times daily by mouth, with a 
range of 2 to 4 Gm. The maximum safe dose is 
4 Gm. and the total dose in 24 hours should not 
exceed 16 Gm. To minimize the gastrointestinal 
disturbances, which are frequent, the dose should 
be administered with meals ; simultaneous use of 5 
to 10 ml. of aluminum hydroxide gel is recom- 
mended. Enteric-coated granules are used to mini- 
mize discomfort. Most patients tolerate the so- 
dium salt better and this salt is used for parenteral 
administration. The calcium salt is also official. 

Storage. — Preserve "in tight, light-resistant 
containers." U.S.P. 

AMINOSALICYLIC ACID TABLETS. 

U.S.P. 

"Aminosalicylic Acid Tablets contain not less 
than 95 per cent and not more than 105 per cent 
of the labeled amount of C7H7NO3." U.S.P. 

Usual Size. — 500 mg. 

AMMONIA 

Fr. Ammoniac (gaz). Ger. Ammoniak; Ammoniakgas. 

One of the most important compounds of nitro- 
gen is ammonia, NH3, a transparent and colorless 
gas possessing an acrid taste and an exceedingly 
pungent odor. From its alkaline reaction and 
gaseous nature it was called the volatile alkali by 
the earlier chemists. Ammonia is the simplest 
form of the class of bodies described as amines, 
and is the prototype of nitrogenous organic bases, 
which may be considered as substituted ammonias. 
The word "ammonia" originated from the fact 
that it was near the temple of the Egyptian deity 
Ammon that the earliest sal ammoniac was found 
as a product originating from camels' urine. Solu- 
tions of ammonia have been known and used 
from very early cimes. The substance itself was 
first recognized by Priestley, who heated the aque- 
ous solution of ammonia and collected the gas 
over mercury. Its components and the proportion 
in which they are combined were determined by 
Berthollet and by Austin. 

Ammonia, either as such or in the form of am- 
monium salts, is found in small quantities in the 
air and in most natural waters; it is a constituent 
in plant and animal fluids and in a few minerals. 
It is formed during the decay of nitrogenous 
organic materials and is an important factor in 
plant nutrition. 

Ammonium compounds are sometimes found in 
sufficient quantity to afford a satisfactory natural 
source. Some of the guano deposits in South 
America contain a considerable proportion of 
ammonium carbonate and have been used as a 



71 



Ammonia 



Part I 



source of ammonia. Volcanic areas frequently 
contain quantities of ammonium chloride and sul- 
fate. However, only a small proportion of the 
commercial supply is obtained from natural 
sources. A considerable quantity of ammonia is 
obtained in the manufacture of illuminating gas, 
power gases, or coke from coal and in the pro- 
duction of shale oil from shale. Some ammonia is 
obtained from the destructive distillation of bones 
and other animal and vegetable wastes. But the 
most important commercial source of ammonia 
today is that of the synthesis of ammonia from 
its constituent elements, nitrogen and hydrogen. 
The techniques of manufacture vary consider- 
ably, but in general the processes consist of a re- 
action between three volumes of hydrogen and 
one volume of nitrogen at pressures between 100 
and 1000 atmospheres and at temperatures rang- 
ing from 400° to 550°, while in contact with a 
promoted iron catalyst. Nitrogen for the reaction 
may be obtained by the distillation of liquid air 
or from the manufacture of producer gas. Hydro- 
gen may be derived from the reaction of natural 
gas with steam in the presence of a nickel catalyst, 
from the electrolysis of brine, or from coke and 
steam by way of the water-gas reaction. The 
German chemist Haber was the first to develop 
a process for synthesis of ammonia from its ele- 
ments as a result of which the method is gener- 
ally designated as the Haber synthetic ammonia 
process. Ammonia may also be obtained from the 
compounds formed by fixation of atmospheric 
nitrogen; thus calcium cyanamide may be made 
to vield it in accordance wath the following reac- 
tion: CaNCN + 3H 2 -> CaCOa + 2NH 3 . 

Ammonia has a specific gravity of 0.597 
(air =1). The gas may be liquefied or solidified; 
the solid melts at — 85°, the liquid boils at 
— 33.4°. It is very soluble in water, a portion 
combining with the water to form ammonium hy- 
droxide. It is easily liquefied by compression. In 
the latter form it is available on the market in 
cylinders. It combines with acids to form salts 
containing the ammonium ion, NH4+, which was 
named by Berzelius. Ammonium ion acts in many 
respects in a manner analogous to the ions of the 
alkaline metals. 

In addition to ammonium salts, ammonia forms 
an interesting series of addition compounds with 
many metallic salts. For instance, the familiar 
deep blue solution obtained when aqueous am- 
monia is added to a cupric salt contains such an 
addition compound. Among the salts which com- 
bine in this manner with ammonia are those of 
silver, zinc, copper, chromium, nickel, cobalt, and 
the platinum metals. Usually two, four, or six 
molecules of ammonia are bound to the metallic 
ion. These compounds were extensively investi- 
gated by Werner; they are known as metal-am- 
monia complexes, Werner's complexes, or ammines 
(not amines, which are organic derivatives). 

The largest peace-time use of ammonia is in 
the manufacture of fertilizers; indeed, ammonia 
is in some areas applied directly to the soil as a 
fertilizer. Ammonia also enters into the manufac- 
ture of many chemicals and such substances as 
rubber, plastics, various synthetic textile fibers, 
. lacquers, etc. It is also employed as a refrigerant. 



In the steel industry it is used to harden steel by 
virtue of its forming a nitride. In time of war 
ammonia is of commanding importance because 
it is the starting point for the manufacture of 
almost all military explosives. 

Physiological Action. — Ammonia is an irre- 
spirable gas; it is so irritant that the instant it 
comes in contact with the glottis is causes imme- 
diate spasm of that orific and inhibition of res- 
piration. Continued exposure to high concentra- 
tions, however, may be sufficiently irritating to 
produce pulmonary edema. Repeated or long- 
continued exposure to low concentrations of the 
gas will cause chronic pulmonary irritation, but 
less than 250 parts per million of the vapor are 
probably harmless. Exposure of the skin to the 
concentrated gas leads to vesicle formation. Its 
only therapeutic value lies in its local irritant 
effects, for it cannot circulate in the blood stream, 
being there converted into ammonium salts. 
Remedial effects of ammonia water or aromatic 
ammonia spirit are due to the evolution of am- 
monia gas which irritates the nasal mucous mem- 
brane, and reflexly stimulates the respiratory and 
vasomotor centers. 

For description of ammonia poisoning, see 
under Diluted Ammonia Solution. For account of 
physiologic properties of ammonium ion see under 
Ammonium Carbonate. 

DILUTED AMMONIA SOLUTION. 
U.S.P. (B.P.) 

Ammonia Water, Diluted Ammonium Hydroxide 
Solution, Liquor Ammonia; Dilutus 

"Diluted Ammonia Solution is a solution of 
NH3 containing, in each 100 ml., not less than 

9 Gm. and not more than 10 Gm. of NH3. Upon 
exposure to air it loses ammonia rapidly." U.S.P. 
The B.P. Dilute Solution of Ammonia contains 

10 per cent w/w (limits, 9.5 to 10.5) of NH3. 

B.P. Dilute Solution of Ammonia. Solution of Ammonia. 
Liquor Ammonii Hydroxidi ; Liquor Ammonii Caustici 
(Ger.); Ammonia Caustica Diluta. Fr. Ammoniaque offi- 
cinale diluee; Solution aqueuse, au dixieme.de gaz am- 
moniac. Ger. Ammoniakfliissigkeit. It. Soluzione di am- 
moniaca. Sp. Solution de Amoniaco Diluida. 

Diluted ammonia solution may be prepared by 
diluting 398 ml. of strong ammonia solution with 
sufficient purified water to make 1000 ml. U.S.P. 

Description. — "Diluted Ammonia Solution is 
a colorless, transparent liquid, having a very 
pungent, characteristic odor. It is alkaline to 
litmus. Its specific gravity is about 0.96." U.S.P. 

Standards and Tests. — Identification. — 
Dense, white fumes are produced when a glass rod 
wet with hydrochloric acid is held near diluted 
ammonia solution. Non-volatile substances. — Not 
over 2 mg. of residue is obtained on evaporating 
10 ml. of diluted ammonia solution and drying at 
105° for 1 hour. Heavy metals. — The limit is 5 
parts per million. Readily oxidizable substances. 
— The pink color of a mixture of 10 ml. of diluted 
ammonia solution with a slight excess of diluted 
sulfuric acid and 0.1 ml. of 0.1 N potassium per- 
manganate does not completely disappear in 10 
minutes. U.S.P. 

The B.P. provides a test for limit of tarry mat- 
ter in which 6 Gm. of powdered citric acid is dis- 



Part I 



Ammonia Solution, Strong 73 



solved in 15 ml. of dilute solution of ammonia: 
no tarry odor is perceptible. The arsenic and 
lead limits are 0.1 and 0.3 part per million, 
respectively. 

Assay. — A portion of 5 ml. of diluted ammonia 
solution is mixed with water and titrated with 1 N 
sulfuric acid, using methyl red T.S. as indicator. 
Each ml. of 1 N sulfuric acid represents 17.03 mg. 
of NH3. U.S.P. In the B.P. assay the ammonia 
solution is weighed into a measured excess of 1 N 
hydrochloric acid; the excess of acid is titrated 
with 1 N sodium hydroxide using methyl red as 
indicator. 

Composition. — Water is capable of dissolving 
large amounts of ammonia; one volume of water 
at 0° and 1 atmosphere dissolves 1298 volumes 
of the gas, and at 20° it dissolves 710 volumes. 
To a large extent the ammonia dissolves as such; 
a portion of it combines chemically with water to 
form the weak base, ammonium hydroxide, which 
dissociates slightly into ammonium and hydroxyl 
ions. Some hydrates of NH3 are also present. 

Incompatibilities. — Ammonium hydroxide re- 
acts with acids to form the corresponding am- 
monium salts and with many metals forms a pre- 
cipitate. Alkaloids are precipitated from solutions 
of their salts. Free iodine may form nitrogen 
iodide which is explosive when dry. 

Uses. — When brought into contact with living 
tissue, ammonia solution acts as a stimulant, irri- 
tant, or caustic according to the concentration of 
the solution. The official diluted ammonia solu- 
tion, if applied for a short time to the skin, pro- 
duces burning pain and redness; if contact is pro- 
longed it is capable of destroying the whole 
dermal tissue. When injected into the circulation, 
diluted ammonia solution produces the character- 
istic effects of ammonium salts but for reasons 
pointed out elsewhere (see under Ammonium 
Carbonate) it cannot be absorbed from the stom- 
ach in sufficient quantity to exercise any direct 
influence upon the general system. It is widely 
used for sudden syncope of nervous origin. By 
the mouth, the effects are due to reflex stimula- 
tion of the vasomotor center from irritation of 
the gastric mucous membrane. Still more marked 
action of the same nature follows smelling of 
ammonia vapor, as from ammonia water (see also 
under Ammonia). If injected hypodermically, the 
resulting pain is a powerful reflex stimulant to 
circulation and respiration. It may cause necrosis 
at the injection site. Although it is an alkali, it is 
too irritant to be useful as a gastric antacid. 

Ammonia water is used as an ingredient of 
stimulating liniments, especially when combined 
with olive or other oil. Under the title Ammonia 
Liniment the N.F. IX recognized a preparation 
made by mixing 10 ml. of oleic acid with 740 ml. 
of sesame oil, adding 250 ml. of diluted ammonia 
solution and agitating until a uniform mixture 
resulted, [v] 

Toxicology. — The symptoms of poisoning by 
ammonia are solely those of local irritation : pain 
in the mouth, throat, and epigastrium; vomiting 
and collapse from the severity of the gastritis. 
Conjunctivitis is common. The conjunctiva should 
be rinsed with water or isotonic sodium chloride 
solution. In some cases the irritation of the throat 



is so severe as to produce an acute edema of the 
glottis which may mechanically obstruct respira- 
tion and cause rapid death from asphyxia. In the 
treatment of the condition, passage of the stom- 
ach tube or the use of emetics is contraindicated 
because of the danger of perforation. Diluted 
acetic acid in the form of vinegar may be used 
as an antidote; olive oil or some other fatty sub- 
stance is useful not only because it combines 
with the caustic alkali to form a comparatively 
nonirritant soap, but also by virtue of its local 
soothing action upon the inflamed mucosa. Mor- 
phine sulfate hypodermically may be used safely 
to relieve pain. In case of edema of the larynx, 
tracheotomy is indicated; it should be realized 
that this condition may not develop for an hour 
or two after the ingestion of the poison and the 
physician should remain ready for immediate 
operation if necessary. The subsequent treatment 
is purely symptomatic. 

Dose, from 0.6 to 2 ml. (approximately 10 to 
30 minims), largely diluted. 

Storage. — Preserve "in tight containers, pref- 
erably at a temperature not above 30°." U.S.P. 

Off. Prep. — Aromatic Ammonia Spirit, U.S.P.; 
Bismuth Magma; Senega Syrup; Washed Sulfur, 
N.F. 

STRONG AMMONIA SOLUTION. 
U.S.P. (B.P.) 

Stronger Ammonia Water, Stronger Ammonium 
Hydroxide Solution, Liquor Ammonias Fortis 

"Strong Ammonia Solution is a solution of 
NH3, containing not less than 27 per cent and not 
more than 30 per cent of NH3. Upon exposure to 
air it loses ammonia rapidly. Caution. — Great care 
should be used in handling Strong Ammonia Solu- 
tion because of the caustic and irritating proper- 
ties of its vapor. Before the container is opened it 
should be well cooled and the closure covered 
with a towel before removal. Strong Ammonia 
Solution must never be tasted nor its vapor in- 
haled." U.S.P. 

The B.P. Strong Solution of Ammonia is more 
concentrated than the U.S.P. solution. It contains 
32.5 per cent w/w of NH3 (limits 31.5 to 33.5). 

B.P. Strong Solution of Ammonia. Sp. Solution de 
Amoniaco Fuerte. 

Strong ammonia solution may be obtained by 
dissolving ammonia gas in water. The solution is a 
complex preparation, containing NH3, hydrates 
of the latter, some NH4OH and small amounts 
of NH 4 + and OH-. 

Description. — "Strong Solution of Ammonia 
is a colorless, transparent liquid, having an ex- 
ceedingly pungent, characteristic odor. It is 
strongly alkaline to litmus. Its specific gravity is 
about 0.90." U.S.P. 

Standards and Tests. — Strong ammonia solu- 
tion, diluted with one and one-half volumes of 
water, meets the requirements of the tests for 
non-volatile substances, heavy metals, and readily 
oxidizable substances under Diluted Ammonia So- 
lution. U.S.P. The B.P. has a test for limit of 
tarry matter (see under Diluted Ammonia Solu- 
tion), and sets the limits of arsenic and lead at 
0.4 and 1 part per million, respectively. 



74 Ammonia Solution, Strong 



Part I 



Assay. — About 2 ml. of strong ammonia solu- 
tion is weighed accurately in a glass-stoppered 
flask containing water and titrated with 1 N sul- 
furic acid, using methyl red T.S. as indicator. 
Each ml. of 1 A T sulfuric acid represents 17.03 mg. 
of NH3. U.S.P. In the B.P. assay the ammonia 
solution is weighed in a flask containing a meas- 
ured excess of 1 N hydrochloric acid; the excess 
of acid is titrated with 1 N sodium hydroxide. 

Great care should be exercised in opening 
bottles containing strong ammonia solution. It is 
safer, if the solution has been kept in a warm 
room, to cool it with ice before attempting to 
withdraw the stopper, as the liberated gas, when 
warm, frequently is forced out under considerable 
pressure, and accidents which have resulted in 
injury to the sight of the operator are recorded. 

Uses. — Strong ammonia solution is too potent 
for medicinal use in its original concentration but 
provides a convenient solution for dilution to the 
strength of ordinary ammonia water. Sufficiently 
diluted with camphor and rosemary spirits, it was 
formerly employed as an irritant lotion for 
alopecia. The inadvertent inhalation of the gas 
escaping from strong ammonia solution may cause 
inflammation of the upper respiratory tract. The 
best antidote, under these circumstances, is the 
inhalation of vapors of vinegar or acetic acid. 
(For toxicology, see under Diluted Ammonia 
Solution.) E 

Dose, 0.2 to 0.4 ml. (approximately 3 to 6 
minims), largely diluted. 

Storage. — Preserve "in tight containers, pref- 
erably at a temperature not above 25°." U.S.P. 

Off. Prep.— Diluted Ammonia Solution, U.S.P., 
B.P.; Ammoniacal Silver Nitrate Solution, N.F.; 
Ammoniated Liniment of Camphor; Aromatic 
Spirit of Ammonia, B.P. 

AROMATIC AMMONIA SPIRIT. 
U.S.P. (B.P.) 

[Spiritus Ammoniac Aromaticus] 

"Aromatic Ammonia Spirit contains, in each 
100 ml., not less than 1.7 Gm. and not more than 
2.1 Gm. of total NH3, and ammonium carbonate, 
corresponding to not less than 3.5 Gm. and not 
more than 4.5 Gm. of (NH^COa." U.S.P. 

The B.P. Aromatic Spirit of Ammonia con- 
tains 1.185 per cent w/v of free ammonia (limits, 
1.12 to 1.25), calculated as NH3, and 3.0 per cent 
w/v of ammonium carbonate (limits, 2.76 to 
3.24), calculated as (NH 4 )2C03. 

B.P. Aromatic Spirit of Ammonia. "Aromatics"; Spirit 
of Sal Volatile. Sp. Espiritu Aromatico de Amoniaco. 

Dissolve 34 Gm. of translucent ammonium car- 
bonate in 90 ml. of diluted ammonia solution and 
140 ml. of purified water by gentle agitation, and 
allow the solution to stand for 12 hours. Dissolve 
10 ml. of lemon oil, 1 ml. of lavender oil and 1 ml. 
of myristica oil in 700 ml. of alcohol contained 
in a graduated bottle or cylinder, and add gradu- 
ally the ammonium carbonate solution along with 
enough purified water to make 1000 ml. Set the 
mixture aside in a cool place for 24 hours, agi- 
tating it occasionally, and then filter, using a 
covered funnel. US.P. 

The B.P. prepares aromatic spirit of ammonia 



by distilling a mixture of alcohol, water, lemon 
oil and nutmeg oil, collecting two portions of 
distillate, the first and larger portion containing 
most of the alcohol and oils, and the second por- 
tion representing largely water saturated with 
oils; the ammonium bicarbonate and stronger 
ammonia water are dissolved in the aqueous frac- 
tion of the distillate and then mixed with the 
distillate representing the hydroalcoholic solution 
of the oils. The B.P. preparation is slightly 
stronger in ammonia water and slightly weaker 
in ammonium carbonate. 

Under ammonium carbonate it was pointed out 
that this substance is a mixture of ammonium 
carbamate and ammonium bicarbonate. In the 
hydroalcoholic medium of aromatic ammonia 
spirit the carbamate dissolves completely and is 
converted by water to carbonate; the bicarbonate, 
however, because of its insolubility in alcohol, 
would be largely precipitated if ammonia were not 
included to convert it to carbonate. This need for 
ammonia is all the more necessary because am- 
monium carbonate which has been exposed to the 
air for a long time will have been in considerable 
part converted to ammonium bicarbonate by loss 
of ammonia; in the presence of ammonia the 
bicarbonate is converted again to carbonate. But 
even with the inclusion of ammonia it is impera- 
tive that translucent pieces af ammonium car- 
bonate be used, for the amount of ammonia may 
be inadequate to convert a large amount of bi- 
carbonate to carbonate, with the result that a 
part of the bicarbonate remains insoluble. The 
U.S.P. allows 12 hours for the reaction between 
ammonia and the components of ammonium car- 
bonate to become completed. If directions are 
followed in every detail, the precipitation (of 
ammonium bicarbonate) sometimes observed will 
not occur. 

Description. — "Aromatic Ammonia Spirit is a 
nearly colorless liquid when recently prepared, but 
gradually acquires a yellow color on standing. It 
has the taste of ammonia, has an aromatic and 
pungent odor, and is affected by light. Its specific 
gravity is about 0.90." US.P. 

The yellow color acquired by the spirit, on 
standing, is due either to alteration of the volatile 
oils, or to a reaction of aldehydes in alcohol in 
the presence of alkali. Despite the change in color, 
the spirit retains its therapeutic activity. 

Assay. — For total ammonia. — A 10-ml. por- 
tion of spirit is diluted with water, mixed with 
30 ml. of 0.5 N sulfuric acid, and the mixture 
boiled until a clear solution results, after which 
the excess of acid is titrated with 0.5 N sodium 
hydroxide, using methyl red T.S. as indicator. 
Each ml. of 0.5 N acid represents 8.516 mg. of 
XH3. For ammonium carbonate. — A second 10-ml. 
portion of spirit is mixed with 30 ml. of 0.5 N 
sodium hydroxide, the mixture boiled until the 
ammonia is expelled and an amount of sodium 
carbonate equivalent to the ammonium carbonate 
originally present is formed, and the solution 
neutralized with 0.5 N sulfuric acid, first to 
phenolphthalein T.S., and then to methyl orange 
T.S. Each ml. of 0.5 N acid consumed in the 
presence of methyl orange represents 48.05 mg. 
of (NH4)2C03. This equivalent is based on the 



Part I 



Ammonium Acetate, Strong Solution of 75 



fact that at the phenolphthalein endpoint the 
carbonate has been converted to bicarbonate, and 
that it is only the latter which is neutralized in 
the presence of methyl orange. 

The B.P. assays for free ammonia by essen- 
tially the same method that the U.S. P. employs 
for total ammonia, except that from the amount 
of acid required to neutralize both free and com- 
bined ammonia is subtracted the amount equiva- 
lent to the ammonium carbonate present. In the 
assay for ammonium carbonate the following 
steps are performed: the sample of spirit is 
treated with a solution of barium chloride to pre- 
cipitate barium carbonate and form an equivalent 
amount of ammonium chloride; simultaneously a 
measured excess of 1 ^ sodium hydroxide is 
added, which reacts with the ammonium chloride 
to form sodium chloride and ammonia; the am- 
monia from this reaction, as well as that present 
in the spirit initially, is reacted with formaldehyde 
to convert it to methenamine; finally, the excess 
of the sodium hydroxide solution is titrated with 
1 N hydrochloric acid, using thymol blue indi- 
cator. Each ml. of 1 N sodium hydroxide repre- 
sents 48.05 mg. of (NEU)2C03. 

Alcohol Content. — From 62 to 68 per cent, 
by volume, of C2H5OH. U.S.P. 

Uses. — Aromatic ammonia spirit is used as a 
mild stimulant in syncope and other forms of 
circulatory weakness. Its action is purely reflex, 
resulting from irritation of the mucous membrane 
of the alimentary tract. Although ammonia is a 
stimulant to the circulation it can act only when 
injected hypodermically. Aromatic ammonia spirit 
has been used for "sick headache." H 

The usual dose is 2 ml. (approximately 30 
minims), well diluted with water. The maximum 
safe dose is usually 4 ml. and the total dose in 24 
hours should seldom exceed 10 ml. 

Storage. — Preserve "in tight, light-resistant 
containers, preferably at a temperature not above 
30°." U.S.P. 

AMMONIUM ACETATE SOLUTION. 
N.F. (B.P.) 

[Liquor Ammonii Acetatis] 

"Ammonium Acetate Solution contains, in each 
100 ml., not less than 6.5 Gm. and not more 
than 7.5 Gm. of CH3COONH4, with small 
amounts of acetic and carbonic acids. Note. — 
Dispense only recently prepared Ammonium 
Acetate Solution." N.F. The B.P. limits of am- 
monium acetate for this solution are from 6.9 to 
7.5 per cent w/v. 

B.P. Dilute Solution of Ammonium Acetate, Liquor 
Ammonii Acetatis Dilutus. Spirit of Mindererus. Am- 
monium Aceticum Solutum; Ammonii Acetas Liquidus; 
Liquor Ammonii Acetici. Fr. Acetate d'ammonium dis- 
sous; Solution officinale d'acetate d'ammonium; Acetate 
d'ammonium liquide. Ger. Ammoniumacetatlosung. It. 
Soluzione di acetato di ammonio. Sp. Acetato de amonio 
liquido; Acetato amonico liquido; Espiritu de minderero. 

Dissolve 50 Gm. of ammonium carbonate, in 
hard, translucent pieces, in sufficient diluted 
acetic acid to make 1000 ml. of solution. Avoid 
strong agitation of the solution during its prepara- 
tion. The solution may also be prepared by mix- 
ing equal volumes of the following solutions: 
Solution No. 1. — Dissolve 100 Gm. of ammonium 



carbonate, in hard, translucent pieces, in suffi- 
cient purified water to make 1000 ml. Solution 
No. 2. — Mix 320 ml. of acetic acid with sufficient 
purified water to make 1000 ml. of solution. N.F. 

The B.P. equivalent of this preparation is made 
by diluting the stronger solution (q.v.) with seven 
parts of distilled water. 

The palatability and compatibility of this solu- 
tion are enhanced by having in it a slight excess 
of acetic acid and carbon dioxide; it is, there- 
fore, important that the ammonium carbonate be 
not decomposed and that the acetic acid be of 
specified strength. Particularly to insure having 
carbon dioxide in the solution as it is dispensed, it 
should be prepared as required for immediate use. 

Description. — "Ammonium Acetate Solution 
is a clear, colorless liquid, free from empyreu- 
matic odor. It has a mildly salty, acid taste, and 
an acid reaction to litmus." N.F. 

Standards and Tests. — Identification. — Am- 
monium acetate solution responds to tests for 
ammonium and for acetate. Residue on ignition. — 
The residue from 20 ml. of solution does not 
exceed 3 mg. N.F. 

Assay. — A portion of 25 ml. is diluted with 
water, made alkaline with sodium hydroxide T.S. 
and the ammonia distilled out of the mixture into 
50 ml. of 1 N sulfuric acid; the excess acid is 
titrated with 1 N sodium hydroxide using methyl 
red T.S. as indicator. Each ml. of 1 A 7 sulfuric 
acid represents 77.08 mg. of CH3COONH4. N.F. 
The B.P. assay is explained under Strong Solution 
of Ammonium Acetate. 

Uses. — Ammonium acetate solution is used as 
a saline diaphoretic and diuretic, especially in 
febrile conditions, [Yl 

Dose, from 15 to 30 ml. (approximately Yi to 1 
fluidounce) every two or three hours, mixed with 
water and sweetened. 

Storage. — Preserve "in tight containers." N.F. 

Off. Prep. — Iron and Ammonium Acetate So- 
lution, N.F. 

STRONG SOLUTION OF AMMONIUM 
ACETATE. B.P. 

Liquor Ammonii Acetatis Fortis 

This solution contains about 57.5 per cent 
w/v of ammonium acetate (limits, 55.0 to 60.0 
per cent) and is prepared by the interaction in an 
aqueous solution of glacial acetic acid, ammonium 
bicarbonate and sufficient strong ammonia solu- 
tion to make the pH of the solution, when a 
portion of it is diluted with 10 volumes of water, 
between 7 and 8 (the test being based on the 
production of a full blue color with bromothymol 
blue solution and a full yellow color with thymol 
blue solution). 

Description and Standards. — The solution 
is described as a thin syrupy liquid having an odor 
of ammonia as well as of acetic acid; the weight 
per ml., at 20°, is about 1.094 Gm. Arsenic and 
lead limits of 4 p.p.m. and 5 p.p.m., respectively, 
are prescribed. 

Assay. — A sample of 5 ml. of solution is 
diluted with water, formaldehyde neutralized to 
phenolphthalein is added, and the solution titrated 
with 1 N sodium hydroxide, using phenolphthalein 



76 Ammonium Acetate, Strong Solution of 



Part I 



solution as indicator. Each ml. of I N sodium hy- 
droxide represents 77.08 mg. of ammonium ace- 
tate. This assay is based on the fact that hydroly- 
sis of ammonium acetate to ammonia and acetic 
acid may be made complete by having formalde- 
hyde present to react with ammonia, forming 
methenamine, and leaving acetic acid to be ti- 
trated with alkalki. 

Dose, from 1 to 4 ml. (approximately 15 to 60 
minims). 

Storage. — Preserve in a bottle made of lead- 
free glass. B.P. 

Off. Prep. — Dilute Solution of Ammonium 
Acetate, B.P. 

AMMONIUM BICARBONATE. B.P. 

Ammonii Bicarbonas 

Ammonium Bicarbonate contains not less than 
98.0 per cent of NH4HCO3. B.P. 

Fr. Carbonate acide d'ammonium. Gcr Ammoniumbicar- 
bonat; Doppeltkohlensaures Ammonium. Sp. Bicarbonato 
amonico. 

Ammonium bicarbonate may be prepared by a 
number of methods. One of these consists in sub- 
liming so-called "ammonium carbonate" (really 
a mixture of ammonium bicarbonate and am- 
monium carbamate; see Ammonium Carbonate) 
in the presence of a little water, a white fibrous 
mass of ammonium bicarbonate, somewhat con- 
taminated with the carbamate, being obtained. By 
washing the mass with alcohol the carbamate is 
dissolved while the bicarbonate remains insoluble. 
Ammonium bicarbonate may also be prepared by 
passing carbon dioxide into an aqueous solution 
of ammonia or by treating "ammonium carbonate'' 
with alcohol in order to remove the carbamate. 

Description and Standards. — Ammonium 
bicarbonate occurs as colorless crystals or a white 
crystalline powder. It is slightly hygroscopic, dis- 
solves in 5 parts of water (at 20°) but is in- 
soluble in alcohol. It volatilizes slowly at room 
temperatures. At 60° it rapidly dissociates into 
ammonia, carbon dioxide and water. It gives the 
characteristic reactions of the ammonium salts 
and of the bicarbonates. 

Pure ammonium bicarbonate does not possess 
the irritant odor of ammonia, but because the 
commercial preparations often contain traces of 
carbamate, ammonia is produced in consequence 
of the dissociation of the latter. According to 
Whittet (Pkarm. J., 1949, 162, 24), solutions of 
ammonium bicarbonate are stable for at least 6 
months if stored in glass-stoppered bottles; ex- 
posed to air the solutions steadily decompose be- 
cause of the release of ammonia and carbon 
dioxide. 

The B.P. includes tests for limits of tarry mat- 
ter, chlorides, sulfates, arsenic, lead and iron. It 
may be assayed by dissolving 2 Gm. in 40 ml. of 
1 N hydrochloric acid, boiling the solution to 
expel carbon dioxide, cooling, and finally titrating 
the excess of acid with 1 N sodium hydroxide 
solution, using methyl red as the indicator. 

Uses. — This drug is very similar in its thera- 
peutic range to the so-called ammonium carbonate 
which is. as a matter of fact, largely composed 
of the bicarbonate. It is somewhat less irritating 



than the older salt since it does not form the basic 
carbonate. It has been used as an expectorant and 
a carminative. 

Externally, ammonium bicarbonate has been 
applied in 0.5 to 2 per cent aqueous solution for 
periodic irrigation of suppurating wounds before 
granulations fill in the wound (see Berezin, Am. 
Rev. Soviet Med., 1945, 2, 230). 

The dose is from 300 to 600 mg. (approxi- 
mately 5 to 10 grains). 

AMMONIUM BROMIDE. N.F. 

[Ammonii Bromidum] 

"Ammonium Bromide, dried at 105° for 2 
hours, contains not less than 99 per cent of 
NHiBr." N.F. 

Ammonium Bromatum; Ammonium Bromuretum; Am- 
monium Hydrobromicum. Fr. Bromure d'ammonium ; 
Bromhydrate d'ammoniaque. Ger. Ammoniumbromid; 
Bromammonium. It. Bromuro di ammonio; Bromidrato di 
aniinoni.ua. Sp. Bromuro de amonio. 

Formerly this salt was prepared by dissolving 
bromine in ammonia water, the hypobromite pro- 
duced being reduced to bromide by means of 
hydrogen sulfide. An early pharmacopeial process 
directed preparation of the salt by the interaction 
of ferrous bromide and ammonia water, the re- 
sulting ferrous hydroxide being oxidized to ferric 
hydroxide and filtered off, and the ammonium 
bromide obtained by evaporation of the filtrate. A 
present-day commercial method of preparing the 
salt involves reaction between boiling solutions 
of ammonium sulfate and potassium bromide; on 
cooling, the potassium sulfate precipitates in part, 
with the remainder separating on concentration of 
the liquid, aided by addition of alcohol. The am- 
monium bromide is obtained from the residual 
liquid by concentrating it to crystallize' the salt. 

Description. — "Ammonium Bromide occurs 
as colorless crystals, or as a yellowish white crys- 
talline powder, having no odor. It is somewhat 
hygroscopic. One Gm. of Ammonium Bromide 
dissolves in about 1.3 ml. of water and in about 
12 ml. of alcohol." N.F. 

Standards and Tests. — Identification. — A 1 
in 10 solution of ammonium bromide responds to 
tests for ammonium and for bromide. Residue 
on ignition. — Not over 0.05 per cent. Acidity. — 
Not more than 0.05 ml. of 0.1 N sodium hy- 
droxide is required to neutralize 2 Gm. of ammo- 
nium bromide in 20 ml. of water, using methyl 
red T.S. as indicator. Chloride. — In the assay, 
each Gm. of ammonium bromide requires not less 
than 101.1 ml. and not more than 103.0 ml. of 
0.1 N silver nitrate in the assay. Sulfate. — No tur- 
bidity is produced in 1 minute on adding barium 
chloride T.S. to a 1 in 20 solution of ammonium 
bromide, acidulated with hydrochloric acid. Ba- 
rium. — No turbidity is produced in 5 minutes on 
adding potassium sulfate T.S. to a 1 in 20 solution 
of ammonium bromide, acidulated with hydro- 
chloric acid. Heavy metals. — The limit is 20 parts 
per million. Iron. — No blue color is produced im- 
mediately on adding potassium ferrocyanide T.S. 
to a 1 in 150 solution of ammonium bromide. 
Bromate. — No yellow color is produced immedi- 
ately on adding diluted sulfuric acid to powdered 
ammonium bromide. Iodide. — Not even a tran- 



Part I 



Ammonium Carbonate 



77 



sient violet color is seen in the chloroform layer 
of a mixture of a 1 in 20 ammonium bromide 
solution, ferric chloride T.S., and chloroform. 
N.F. 

Assay. — A sample of about 400 mg. of ammo- 
nium bromide, previously dried at 105° for 2 
hours, is assayed by the Volhard method, in 
which a measured excess of 0.1 A T silver nitrate 
is employed; the excess silver ion is determined 
by titration with 0.1 N ammonium thiocyanate, 
using ferric ammonium sulfate T.S. as indicator. 
Each ml. of 0.1 N silver nitrate represents 
9.796 mg. of NH 4 Br. N.F. 

Uses. — Ammonium bromide is useful chiefly 
for the action of bromide ion (see under Potas- 
sium Bromide). It has a disagreeable taste and 
may cause digestive disturbances. According to 
Dressier {Clinical Cardiology, 1942, p. 186) it is 
preferable to ammonium chloride in treatment 
of edema of cardiac origin, being better tolerated 
and having the two-fold action of being sedative 
to the central nervous system and producing aci- 
dosis as an adjuvant to mercurial diuresis. For 
such purpose it is administered in doses of 1 Gm. 
four times a day for two days before injection 
of the mercurial. 

Dose, 0.6 to 2 Gm. (approximately 10 to 30 
grains) well diluted. 

Storage. — Preserve "in tight containers." 
N.F. 

Off. Prep. — Five Bromides Elixir; Bromides 
Syrup; Three Bromides Elixir; Three Bromides 
Tablets, N.F. 



AMMONIUM CARBONATE. 

[Ammonii Carbonas] 



U.S.P. 



"Ammonium Carbonate consists of ammonium 
acid carbonate (NH4HCO3) and ammonium car- 
bamate (NH2.COO.NH4) in varying proportions, 
and yields not less than 30 per cent and not more 
than 33 per cent of NH3." U.S.P. 

Ammonia Crystal; Sal Volatile. Ammoniae Carbonas; Am- 
monium Carbonicum; Ammonium Sesquicarbonicum. Fr. 
Carbonate d'ammonium officinal; Sesquicarbonate d'am- 
moniaque; Alcali volatil concret. Ger. Ammoniumkarbonat ; 
Kohlensaures Ammonium; Hirschhornsalz; Fluchtiges Salz. 
It. Carbonato di ammonio. Sp. Carbonato de amonio. 

As is apparent from the official definition, "am- 
monium carbonate" is in reality a mixture of am- 
monium bicarbonate and ammonium carbamate. 
The salt is prepared by heating a mixture of am- 
monium chloride and calcium carbonate in iron 
pots or retorts; the "ammonium carbonate" vapor 
is condensed and the ammonium vapor is con- 
ducted into an acid solution. The reaction may be 
represented as follows: 

4NH4C1 + 2CaCOs -> NH4HCO3.NH2COONH4 
+ NH 3 + 2CaCl 2 + H2O 

Ammonium carbonate can also be prepared by 
direct reaction of ammonia, carbon dioxide and 
steam. 

Description. — "Ammonium Carbonate occurs 
as a white powder or as hard, white or translucent 
masses, having a strong odor of ammonia, with- 
out empyreuma, and with a sharp, ammoniacal 
taste. Its solutions are alkaline to litmus. On ex- 
posure to air, it loses ammonia and carbon dioxide, 



becoming opaque, and is finally converted into 
friable, porous lumps or a white powder of am- 
monium bicarbonate. One Gm. of Ammonium 
Carbonate dissolves very slowly in about 4 ml. 
of water. It is decomposed by hot water." U.S.P. 

Standards and Tests. — Identification. — Am- 
monium carbonate volatilizes without charring 
when heated; the vapor is strongly alkaline to 
moistened litmus paper. Solutions of ammonium 
carbonate effervesce with acids. Residue on igni- 
tion. — Not over 0.05 per cent. Chloride. — The 
limit is 35 parts per million. Sulfate. — The limit 
is 50 parts per million. Heavy metals. — The limit 
is 10 parts per million. Emypreumatic matter. — 
A colorless, odorless residue is obtained on evapo- 
rating to dryness on a water bath a nitric acid 
solution of 1 Gm. of ammonium carbonate. U.S.P. 

If official ammonium carbonate is treated with 
90 per cent alcohol, it is resolved into the two 
salts of which it is composed, ammonium car- 
bamate going into solution while the acid ammo- 
nium carbonate remains undissolved. The latter 
compound also remains undissolved when the com- 
mercial carbonate is treated with an amount of 
water insufficient for complete solution. Upon 
complete solution of the salt in water there re- 
sults a mixture of acid and neutral carbonates, 
the carbamate having undergone hydrolysis ac- 
cording to the equation: 

NH2.COO.NH4 + H2O -» (NHO2CO3 

Boiling the aqueous solution results in decomposi- 
tion of the compound into ammonia and carbon 
dioxide. 

Exposed to air, ammonium carbonate is gradu- 
ally converted into bicarbonate, becoming opaque 
and friable, and changing to powder form. 

Assay. — A sample of about 2 Gm. of am- 
monium carbonate is dissolved in 50 ml. of 1 N 
sulfuric acid, and the excess of acid is titrated 
with 1 A T sodium hydroxide, using methyl orange 
T.S. as indicator. Each ml. of 1 A 7 sulfuric acid 
represents 17.03 mg. of NH3. U.S.P. 

Uses. — Locally ammonium carbonate is an 
active irritant capable of causing gastritis. Sys- 
temically its action is that of its ammonium 
radical. When injected intravenously, in experi- 
mental studies (since it is not injected in thera- 
peutics), the blood pressure increases, partly from 
an effect on the cardiac muscles, and probably 
also in part from a stimulation of the vasomotor 
center in the medulla: the pressure returns to 
normal in a very few minutes. After toxic doses 
the rise may be followed by a fall to a point below 
normal. There is an increase in the rapidity of 
breathing due to an action upon the respiratory 
center. The action upon the spinal cord is shown 
by increased activity of reflexes; in sufficient 
doses it is capable of causing tetanic convulsions. 
These effects are caused only when ammonium 
carbonate is injected rapidly. When the drug is 
taken by mouth, the ammonium ion is so rapidly 
destroyed in the system that it is scarcely possi- 
ble for a sufficient quantity to be absorbed through 
the mucous membrane of the alimentary tract. 
It is oxidized in the liver and appears in the 
urine chiefly as urea (see also under Ammonium 
Chloride) . 



m 



78 



Ammonium Carbonate 



Part I 



Ammonium carbonate has been used as a car- 
minative in "sick headache." It is also employed 
as an expectorant in the same type of bronchitis 
in which ammonium chloride is used; the car- 
bonate will obviously be converted to chloride in 
the stomach and its action will therefore be that 
of the chloride. Coarsely pulverized and mixed 
with half its bulk of stronger ammonia water, and 
usually scented with oil of lavender, it constitutes 
the common smelling salts so frequently held 
under the nostrils as stimulant in syncope and 
nervous collapse. It is unlikely that sufficient am- 
monia can be absorbed through the mucous mem- 
brane to exert any physiological action, and as 
the gas is irrespirable it cannot be inhaled. The 
beneficial action, which undoubtedly occurs in 
many patients, is probably due to a reflex effect 
from irritation of the nasal mucous membrane. 
Acetic acid vapors are used for the same purpose. 
A similar result is obtained by swallowing a solu- 
tion of ammonium carbonate, as in the popular 
aromatic ammonia spirit, although in this case 
the reflex comes from irritation of the stomach 
instead of the nose. EO 

Ammonium carbonate, under the name baker's 
ammonia, is sometimes used as a leavening agent, 
replacing sodium bicarbonate. 

The usual dose is 300 nig. (approximately 5 
grains) in dilute solution. The maximum safe dose 
is usually 600 mg. and the total dose in 24 hours 
should seldom exceed 2 Gm. 

Storage. — Preserve "in tight containers, pref- 
erably at a temperature not above 30°, protected 
from' light." U.S.P. 

Off. Prep. — Aromatic Ammonia Spirit, U.S.P., 
Ammonium Acetate Solution; Bismuth Magma; 
Expectorant Mixture, N.F. 

AMMONIUM CHLORIDE. U.S.P., B.P. 

[Ammonii Chloridum] 

"Ammonium Chloride, dried over sulfuric acid 
for 4 hours, contains not less than 99.5 per cent 
of NH4CI." U.S.P. The B.P. requires not less 
than 99.5 per cent of NH4CI, calculated with 
reference to the substance dried in a vacuum 
desiccator over sulfuric acid for 24 hours. 

Muriate of Ammonia. Ammonium Muriaticum; Am- 
monium Chloratum; Ammonium Chloruretum; Ammonium 
Hydrochloricum; Chlorhydras Ammoniac; Ammonii Chlor- 
urum. Fr. Chlorure d'ammoniurn; Chlorhydrate d'am- 
moniaque; Sel ammoniac. Ger. Ammoniumchlorid; Salmiak. 
It. Cloruro di ammonio. Sp. Cloruro de amonio. 

Ammonium chloride originally came from 
Egypt, where it was obtained by sublimation 
from the soot resulting from the burning of 
camels' dung, which was used in that country for 
fuel. The name sal ammoniac, by which it was 
first known, is derived from the fact that it was 
largely obtained in the Libyan desert near the 
temple of Jupiter Ammon. Ammonium chloride 
has long been known in China, where it is obtained 
from the water of certain volcanic springs. It is 
found in the fumaroles of Vesuvius, Etna, Hecla, 
and other volcanoes, and in the cracks and fissures 
in recent lava streams. 

Ammonium chloride is commonly prepared by 
passing ammonia into hydrochloric acid. Chief 
source of the ammonia is ammoniacal gas liquor 



(see Ammonia), from which a reasonably pure 
ammonia may be distilled after treatment with 
lime. Purification of the ammonium chloride 
may be effected by subliming the salt. Ammonium 
chloride may also be prepared by the interaction 
of ammonia and hydrogen chloride vapors in the 
presence of some water. For other methods which 
have been used see U.S.D., 23rd edition. 

Description. — "Ammonium Chloride occurs 
as colorless crystals or as a white, fine or coarse, 
crystalline powder. It has a cool, saline taste, 
and is somewhat hygroscopic. One Gm. of Ammo- 
nium Chloride dissolves in 2.6 ml. of water, in 
about 100 ml. of alcohol, and in about 8 ml. of 
glycerin. One Gm. of it dissolves in 1.4 ml. of 
boiling water." U.S.P. 

Standards and Tests. — Identification. — A 1 
in 10 solution of ammonium chloride responds to 
tests for ammonium and for chloride. Loss on 
drying. — Not over 0.5 per cent, when dried over 
sulfuric acid for 4 hours. Residue on ignition. — 
Not over 0.1 per cent, on igniting a mixture of 1 
ml. of sulfuric acid and 2 Gm. of ammonium 
chloride. Acidity. — Not more than 0.05 ml. of 
0.1 N sodium hydroxide is required to neutralize 
2 Gm. of ammonium chloride in 20 ml. of water, 
using methyl red T.S. as indicator. Thiocyanate. 
— Addition of a few drops of ferric chloride T.S. 
to a 1 in 10 solution of ammonium chloride, acidu- 
lated with hydrochloric acid, does not produce 
a red color. Heavy metals. — The limit is 10 parts 
per million. U.S.P. The B.P. limits loss on drying 
to 1.0 per cent, arsenic to 4 parts per million, 
and lead to 5 parts per million. 

Assay. — About 200 mg. of ammonium chlo- 
ride, previously dried over sulfuric acid for 4 
hours, is assayed by a modification of the Volhard 
method in which an excess of 0.1 N silver nitrate 
is added, and the excess of silver ion titrated 
directly, without filtering off the silver chloride, 
with 0.1 N ammonium thiocyanate, using ferric 
ammonium sulfate T.S. as indicator. The modifi- 
cation consists in adding 3 ml. of nitrobenzene 
prior to the titration with ammonium thiocyanate 
solution; the former coats the particles of silver 
chloride so that they will not react with the 
thiocyanate (see Caldwell and Moyer, Ind. Eng. 
Chem., Anal. Ed., 1935, 7, 38). Each ml. of 0.1 A T 
silver nitrate represents 5.350 mg. of NH4CI. 
U.S.P. 

The B.P. utilizes the classical Volhard assay, 
the silver chloride being removed by filtration 
before titrating with thiocyanate. 

Incompatibilities. — Ammonium chloride is 
incompatible with lead and silver salts, producing 
precipitates respectively of lead and silver chlo- 
rides. With alkalis, as well as with substances 
which in aqueous solution produce an alkaline 
reaction, ammonia is liberated. This incompati- 
bility is shared by all ammonium salts. 

Uses. — Ammonium chloride is most commonly 
used as an expectorant and as a diuretic; it is an 
excellent systemic acidifying agent. It possesses 
the stimulant qualities of its basic ion and re- 
sembles the carbonate in its physiologic action. 

Acidifying and Diuretic Actions. — Systemic 
effects of ammonium chloride depend upon the 
ability of the liver to convert ammonium ion into 



Part I 



Ammonium Chloride 



79 



urea, thus liberating the anion into the blood 
stream and into extracellular fluids. For this rea- 
son all the inorganic salts of ammonium increase 
the acidity of the urine. One gram of ammonium 
chloride is as effective as a urinary acidifier as 
2.5 Gm. of sodium acid phosphate (see J. A.M. A., 
1951, 147, 207). It is used, therefore, in those 
types of urinary tract infection where a low uri- 
nary pH is desired, in doses of 6 to 8 Gm. (ap- 
proximately V/i to 2 drachms) daily. It is some- 
times administered in conjunction with methena- 
mine. 

According to Cornbleet (J.A.M.A., 1951, 146, 
1116), the excess chloride that is liberated filters 
through the kidney glomeruli, which the tubules 
refuse to reabsorb from the filtrate. Some of the 
chloride is neutralized by sodium, potassium and 
calcium. Compensatory factors acting through the 
posterior lobe of the pituitary body and the 
adrenal cortex cause an equivalent amount of 
water to leave with the sodium, increasing urine 
formation and promoting diuresis. Grollman states 
that the acidosis produced by ammonium chloride 
causes the passage of intracellular salts and water 
into the extracellular spaces, with elimination of 
this tissue fluid by the kidney (see Modern Medi- 
cine, June 1, 1951, p. 59). 

One of the uses of the acidifying quality of this 
drug is based on the observation of Aub, Minot 
and Reznikoff (Medicine, 1925, 4, 1) that diminu- 
tion of the pH of the circulating blood renders 
calcium more soluble, thus promoting decalcifica- 
tion. In lead poisoning the stored lead accom- 
panies calcium. It is possible, therefore, to "de- 
lead" a patient with lead poisoning by the admin- 
istration of ammonium chloride in 1 Gm. (ap- 
proximately 15 grains) doses each hour 8 to 10 
times daily, together with a diet poor in calcium 
and rich in phosphorus. It has been noted by 
Brown, Kolmer and Rule (Am. J. Syph., 1943, 
27, 501) that stored bismuth, resulting from its 
injection for the treatment of syphilis, may be 
similarly mobilized, but toxic reactions may be 
encountered. 

A frequent use of ammonium chloride is to 
promote diuresis in many conditions characterized 
by edema, as in the nephrotic syndrome, portal 
cirrhosis of liver, and congestive heart failure. 
Dosage is 4 to 12 Gm. (approximately 1 to 3 
drachms) daily, in divided quantities, with meals, 
usually as enteric-coated tablets. It is ordinarily 
given in courses of 3 days, with equal rest periods 
to minimize gastric irritation and diarrhea. In 
the edema of congestive heart failure it is popu- 
larly administered for 48 to 72 hours prior to 
giving a mercurial diuretic to enhance the effect 
of the latter (Etheridge, Arch. Int. Med., 1936, 
57, 514). Stock et al. (Circulation, 1951, 4, 54) 
state that its synergistic effect when so used is 
probably due to its ability to prevent or counter- 
act alkalosis. Schroeder (J.A.M.A., 1951, 147, 
1109) attributes the synergism to the fact that the 
acidic salts cause osmotic tubular diuresis as well 
as increasing the renal excretion of bases, includ- 
ing sodium. It has been found by Greiner and 
Gold (JAM. A., 1953, 152, 1130) that even in a 
dose of 16 Gm. ammonium chloride is less effec- 
tive as a diuretic than are orally administered 



theophylline salts and organic mercurials. Addi- 
tional diuretic indications for ammonium chloride 
include treatment of premenstrual tension, ther- 
apy of Meniere's syndrome in conjunction with a 
neutral diet (Furstenburg et al, Ann. Otol. Rhin. 
Laryng., 1934, 43, 1035), and in certain alcoholic 
states. Cornbleet (loc. cit.) treated bromide intoxi- 
cation successfully with ammonium chloride, since 
this salt furnishes chloride to displace the bromide 
and is simultaneously a diuretic. 

Zintel, Rhoads and Ravelin (Surgery, 1943, 14, 
728) reported intravenous use of ammonium 
chloride in alkalosis. They used a 2 per cent 
solution in normal saline or in 5 per cent dextrose, 
the maximum rate of injection being 1 liter in 
2 hours. A 1-Gm. dose is said to reduce the serum 
carbon dioxide-combining power in a 150-pound 
adult by 1.1 volume per cent. The solution in 
saline may be autoclaved for 20 minutes at 15 
pounds pressure. No serious reaction is reported 
although there may be chill or fever. 

Expectorant Action. — Ammonium chloride is 
widely prescribed as an expectorant. Being non- 
volatile it is not exhaled through the pulmonary 
alveoli. It is believed that reflex stimulation of 
the bronchial mucous glands results from irrita- 
tion of the gastric mucosa. Perry and Boyd 
(/. Pharmacol., 1941, 73, 65) demonstrated an 
increase in bronchial secretion by reflex action 
from the stomach, there being no response to 
introduction of ammonium chloride after severing 
branches of the vagus nerve supplying the 
stomach. Banyai states (J.A.M.A., 1952, 148, 
501) that, in addition to reducing viscosity and 
pH and increasing fluidity of the bronchial secre- 
tions, the drug stimulates the ciliary function of 
the mucosa. A dose of 300 mg. every 2 hours is 
used in a syrup; tablets should not be enteric- 
coated. Flavored lozenges containing the drug are 
sometimes prescribed in pharyngitis and laryngitis 
to secure both a local effect and an effect from 
the medicated saliva that is swallowed. 

Local Anesthetic Action. — A new use for 
ammonium chloride has been described by Judo- 
vich, Bates and Bishop (Anesth., 1944, 5, 341), 
based on earlier investigation of a preparation of 
the pitcher plant, Sarracenia purpurea, made by 
distillation of the powdered rhizome in the pres- 
ence of caustic alkali and used in the relief of 
neuralgic pain. Neutralization of the distillate 
with hydrochloric or sulfuric acid yields salts 
found to be identical with ammonium chloride 
and ammonium sulfate, respectively (see Stewart 
et al, Am. J. Physiol, 1940, 129, 474; Walti, 
J.A.C.S., 1945, 67, 2271). Following preliminary 
sedation of the patient with morphine, atropine 
and amytal, from 3 to 5 ml. of a 6 per cent solu- 
tion of ammonium chloride, adjusted to pH 7.2 
by means of sodium hydroxide, is mixed with 
50 ml. of cerebrospinal fluid and injected intra- 
spinally. Such administration is limited to patients 
with root pain of metastatic origin. 

Toxicology. — Among the more severe toxic 
reactions to ammonium chloride, acidosis has 
been reported by Sleisinger and Freedberg (Circu- 
lation, 1951, 3, 837), during its administration 
as a diuretic. They believed the severe acidosis 
to be related to intrinsic renal disease and the 



80 



Ammonium Chloride 



Part I 



inability of the kidneys to prevent continued loss 
through the urine of fixed base with chloride. The 
drug may also precipitate uremia when used in 
the presence of renal disease. 

According to Purdum (7. A. Ph. A., 1942, 31, 
298) syrups of glycyrrhiza, raspberry, orange 
flowers, citric acid and tolu balsam are the most 
effective masking vehicles for the disagreeable 
salty taste of ammonium chloride. An aromatic 
syrup of ammonium chloride, prepared by Sorg 
and Kuever (/. A. Ph. A., Pract. Ed., 1942, 3, 
262) especially for use in Furstenberg's treatment 
of Meniere's disease, has the following composi- 
tion: Ammonium chloride, 200 Gm.; soluble sac- 
charin, 10 Gm.; menthol, 1 Gm.; alcohol, 30 ml.; 
glycerin, 100 ml.; compound syrup of sarsaparilla, 
400 ml.; distilled water, to 1000 ml. (3 

The usual dose is 1 Gm. (approximately 15 
grains), by mouth, 4 times a day, with a range 
of 300 mg. to 2 Gm.; the maximum safe dose is 
2 Gm., and the total dose in 24 hours exceeds 
8 Gm. only under certain conditions (v.s.). As 
an expectorant, 300 mg. (approximately 5 grains) 
is used as frequently as every two hours. 

Storage. — Preserve "in tight containers." 
U.S.P. 

AMMONIUM CHLORIDE CAPSULES 

U.S.P. 

[Capsulse Ammonii Chloridi] 

"Ammonium Chloride Capsules contain not less 
than 93 per cent and not more than 107 per cent 
of the labeled amount of NH4CI." U.S.P. 

Sp. Cdpsulas de Cloruro de Amonxo. 

Assay. — The contents of not less than 20 cap- 
sules are transferred to a 500-ml. volumetric 
flask, the emptied capsules being washed with 
water and this solution filtered into the same 
volumetric flask. After diluting to 500 ml. an 
aliquot portion, equivalent to about 200 mg. of 
ammonium chloride, is transferred to a distilling 
flask, alkalinized with 10 per cent sodium hydrox- 
ide solution, and the ammonia distilled into a 
boric acid solution. The ammonia in this solution 
is titrated with 0.1 N sulfuric acid, using methyl 
red T.S. as indicator. A blank test is performed 
on the reagents and any necessary correction ap- 
plied. Each ml. of 0.1 N sulfuric acid represents 
5.350 mg. of NH4CI. U.S.P. 

Storage. — Preserve "in tight containers." 
U.S.P. 

Usual Sizes. — 5 and l l /z grains (approxi- 
mately 300 and 500 mg.). 

AMMONIUM CHLORIDE TABLETS. 
N.F. 

[Tabellae Ammonii Chloridi] 

"Ammonium Chloride Tablets contain not less 
than 94 per cent and not more than 106 per cent 
of the labeled amount of NH4CI for tablets of 
300 mg. or more, and not less than 92.5 per cent 
and not more than 107.5 per cent for tablets of 
less than 300 mg." N.F. 

Usual Sizes. — 5 and lYz grains (approxi- 
mately 300 and 500 mg.), frequently enteric 
coated. 



AMMONIUM IODIDE. N.F. 

[Ammonii Iodidum] 

"Ammonium Iodide dried at 105° for 2 hours 
contains not less than 98 per cent of NH4I. It 
may contain not more than one per cent of am- 
monium hypophosphite as a stabilizing agent." 
N.P. 

Ammonium Jodatum; Jodetum Ammonicum; Ammonium 
Hydrojodicum. Fr. Jodure d'ammonium. Ger. Ammonium- 
jodid; Jodammonium. It. Joduro di amnionic Sp. Voduro 
de amonio. 

Several methods of preparing ammonium iodide 
are available. The one probably most often em- 
ployed is that involving the interaction of am- 
monium sulfate and potassium iodide; the potas- 
sium sulfate precipitates on cooling the mixture 
and adding some alcohol to it, and the ammonium 
iodide is obtained on evaporating the liquid phase. 
Other methods of making ammonium iodide in- 
volve neutralization of hydriodic acid by am- 
monia, interaction between ferrous iodide and 
ammonium carbonate, or between potassium 
iodide and ammonium bitartrate. 

Description. — "Ammonium Iodide occurs as 
minute, colorless, cubic crystals, or as a white, 
granular powder. It is odorless, and has a sharp, 
salty taste. Ammonium Iodide is very hygro- 
scopic, and soon becomes yellow or yellowish 
brown on exposure to air and light, owing to the 
loss of ammonia and the liberation of iodine, if no 
stabilizing agent is added. Its solutions are neutral 
or acid to litmus paper. One Gm. of Ammonium 
Iodide dissolves in about 0.6 ml. of water, in 
about 3.7 ml. of alcohol, and in about 1.5 ml. of 
glycerin, at 25°. One Gm. also dissolves in about 
0.5 ml. of boiling water." N.F. 

Standards and Tests. — Identification. — A 1 
in 20 solution of ammonium iodide responds to 
tests for ammonium and for iodide. Loss on dry- 
ing. — Not over 5 per cent, when dried at 105° for 
2 hours. Residue on ignition. — Not over 0.5 per 
cent (strong heating decomposes the salt with 
evolution of iodine vapor and volatilization with- 
out fusing). Chloride. — In the assay, each Gm. of 
ammonium iodide consumes not less than 67.6 ml. 
and not more than 69.0 ml. of 0.1 N silver nitrate. 
Free iodine. — Not even a transient violet color 
appears in chloroform when it is shaken with 
5 volumes of 1 in 150 solution of ammonium 
iodide. Barium. — No turbidity is produced in 5 
minutes on adding a 1 in 10 solution of sodium 
sulfate to 5 volumes of a 1 in 20 solution of am- 
monium iodide which has been acidulated with 
hydrochloric acid. Heavy metals. — The limit is 
20 parts per million. N.F. 

Assay. — The Volhard method is employed in 
assaying ammonium iodide; an excess of 0.1 N 
silver nitrate is added to about 500 mg. of am- 
monium iodide, previously dried at 105° for 2 
hours, the mixture heated until the precipitate 
has a yellow color and, after cooling, the residual 
silver nitrate is estimated by titration with 0.1 N 
ammonium thiocyanate using ferric ammonium 
sulfate T.S. as indicator. Each ml. of 0.1 N silver 
nitrate represents 14.50 mg. of NH4I. N.F. 

Uses. — Ammonium iodide has been used like 
potassium iodide (see Potassium Iodide, also 



Part I 



Amobarbital 



81 



Iodine). It was especially recommended in chronic 
bronchitis and in asthma, with the thought of 
combining the resolvent action of the iodide and 
the expectorant effect of ammonium. Pennock 
used it in cases of lepra and psoriasis, in the form 
of a 4 to 12 per cent ointment. As the iodide is 
decomposed by air, the ointment should be kept 
in well-stoppered bottles. |v] 

Dose, from 200 to 600 mg. (approximately 3 to 
10 grains). 

Storage. — Preserve "in tight, light-resistant 
containers." N.F. 



AMMONIUM SALICYLATE. N.F. 

[Ammonii Salicylas] 

"Ammonium Salicylate, dried over sulfuric 
acid for 4 hours, contains not less than 98 
per cent of C7H5NH4O3." N.F. 

Ammonium Salicylicum. Fr. Salicylate d'ammonium. 
Ger. Ammoniumsalicylat; Salicylsaures Ammonium. It. 
Salicilato di ammonio. Sp. Salicilato de amonio. 

This salt may be made by adding salicylic 
acid to ammonia water until the acid is in slight 
excess, then evaporating the solution and crystal- 
lizing. Contamination with iron gives the product 
a pinkish or reddish tinge; overheating results in 
the salt having a phenol-like odor. 

Description. — "Ammonium Salicylate occurs 
as colorless, lustrous prisms, or plates, or as a 
white crystalline powder having a faint pink 
tinge. It is odorless, and has at first a slightly 
salty, bitter taste, with a sweet aftertaste. It is 
stable in dry air, but is affected by light. One 
Gm. of Ammonium Salicylate dissolves in about 
1 ml. of water and in about 3 ml. of alcohol." N.F. 

Standards and Tests. — Identification. — Am- 
monium salicylate responds to tests for ammonium 
and for salicylate. Acidity. — Not more than 0.4 
ml. of 0.1 N sodium hydroxide is required to 
neutralize 1 Gm. of ammonium salicylate, using 
methyl red T.S. as indicator. Residue on ignition. 
— Not over 0.05 per cent. Heavy metals. — The 
limit is 10 parts per million. N.F. 

Assay. — About 500 mg. of ammonium salicyl- 
ate, previously dried over sulfuric acid for 4 
hours, is titrated with 0.1 iV hydrochloric acid in 
the presence of ether. The acid displaces sali- 
cylic acid which dissolves in the ether layer; an 
equivalent amount of ammonium chloride is 
formed in the aqueous phase. Because a small 
amount of salicylic acid remains dissolved in the 
aqueous phase it is necessary, when the first 
end-point is reached, to replace the ether layer 
by a fresh portion of ether to extract the salicylic 
acid in the aqueous layer; the titration is con- 
tinued until the bromophenol blue indicator shows 
a permanent pale green color in the aqueous layer. 
Each ml. of 0.1 N hydrochloric acid represents 
15.52 mg. of C7H5NH4O3. N.F. 

Uses. — Ammonium salicylate was at one time 
thought to be one of the best forms of adminis- 
tering salicylic acid internally but it is seldom 
used at present. For discussion of its uses, see 
under Acetylsalicylic Acid and Sodium Salicylate. 

Dose, from 0.6 to 1.3 Gm. (approximately 10 
to 20 grains). 



Storage. — Preserve "in tight, light-resistant 
containers, and avoid excessive heat." N.F. 

AMOBARBITAL. U.S.P. 

5-Ethyl-5-isoamylbarbituric Acid, [Amobarbitalum] 



HN 
HN 



y~\w s 



^/^CHgCHgCHtCH^j 



Amylobarbitone, B.P.C. Amytal (Lilly). 

Amobarbital may be prepared by the general 
procedure for producing barbiturates, namely, by 
condensation of the proper substituted malonic 
ester with urea; in this instance the ester is 
isoamylethylmalonic ester. Condensation is ef- 
fected in an autoclave in the presence of sodium 
ethylate (see Shonle and Moment, J.A.C.S., 1923, 
45, 243; U. S. Patent 1,514,573, November 4, 
1924). 

Description. — "Amobarbital occurs as a 
white crystalline powder. It is odorless and has a 
bitter taste. Its solutions are acid to litmus paper. 
One Gm. of Amobarbital dissolves in about 
1300 ml. of water, in 5 ml. of alcohol, in about 
17 ml. of chloroform, and in 6 ml. of ether. It is 
soluble in solutions of fixed alkali hydroxides and 
carbonates. Amobarbital melts between 156° and 
158.5°. U.S.P. 

Standards and Tests. — Identification. — (1) 
Ammonia is evolved on heating amobarbital with 
sodium hydroxide T.S. (2) The />-nitrobenzyl 
derivative melts between 151° and 154°. Loss 
on drying. — Not over 1 per cent, when dried over 
sulfuric acid for 4 hours. Residue on ignition. — 
Not over 0.1 per cent. Readily carbonizable sub- 
stances. — A solution of 500 mg. of amobarbital 
in 5 ml. sulfuric acid has no more color than 
matching fluid A. U.S.P. 

Uses. — Amobarbital, introduced as Amytal, is 
a barbiturate of moderate duration of action. It 
has the advantage over barbital and phenobarbi- 
tal of being destroyed in the body and since its 
elimination does not depend on the kidneys amo- 
barbital is preferable to the two other barbitu- 
rates for administration to patients with kidney 
disease. For a comparison of duration of action 
and metabolism of amobarbital see the mono- 
graph on Barbiturates, in Part II. 

For parenteral administration the water-soluble 
sodium derivative, in sterile form, is employed; 
the latter may also be given orally and, some- 
times, rectally. Amobarbital sodium is the drug 
of choice when a longer period of action is de- 
sired during the gradual induction of narcosis 
in a patient to be interviewed by the technique 
of "narcosynthesis" or "narcoanalysis" (see also 
under Thiopental Sodium) ; for a review of this 
use of amobarbital sodium see Lipton {American 
Practitioner, 1950, 1, 148). According to Miller 
{Arch. Neurol. Psychiat., 1952, 67, 620) simulta- 
neous use of ethyl alcohol improves the incidence 
of success in narcoanalysis by decreasing somno- 
lence and increasing talkativeness while also 
decreasing the dose of amobarbital sodium re- 



82 



Amobarbital 



Part I 



quired; from 120 to 300 mg. of amobarbital 
sodium, depending on the weight of the patient, 
is dissolved in 20 to 25 ml. of isotonic sodium 
chloride solution containing 10 to 15 per cent 
of alcohol and the solution administered intrave- 
nously over a period of 2 to 4 minutes. 

Its moderate vasodepressor effect seems to be 
useful for the purpose of diagnosing phenochro- 
mocytoma (Anderson et al., Am. Heart J., 1952, 
43, 252). 

Administered intravenously (230 to 500 mg.), 
amobarbital sodium produced a significant de- 
pression of oxygen uptake by the brain, a lower- 
ing of blood flow, and a mild depression of mean 
arterial pressure in the eclamptic patient; this 
may be an advantage in the preeclamptic patient 
for the prevention of seizures but may add to the 
depression produced by convulsions in the ad- 
vanced case (McCall and Tavlor, J.A.M.A., 1952, 
149, 51). 

Combined with amphetamine, amobarbital has 
been reported to neutralize extremes of moods, 
giving the depressed patient a more normal out- 
look and behavior (Grahn, American Practitioner , 
1950, 1, 795). 

The usual dose of amobarbital is 100 mg. (ap- 
proximately iy 2 grains) once or twice daily, by 
mouth, with a range of 20 to 300 mg. The maxi- 
mum safe dose is usually 500 mg.. and the total 
dose during 24 hours should seldom exceed 1 Gm. 
When used as a sedative it is given in doses of 
20 to 50 mg.; as a hypnotic the dose is 100 to 
300 mg. 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

AMOBARBITAL ELIXIR. N.F. 

[Elixir Amobarbitali] 

"Amobarbital Elixir contains, in each 100 ml., 
not less than 417 mg. and not more than 462 mg. 
of CiiHi 8 N 2 3 ." N.F. 

Dissolve 4.4 Gm. of amobarbital, 1 Gm. of sac- 
charin sodium, 0.26 ml. of orange oil, 0.15 ml. 
of lemon oil, 0.03 ml. of cinnamon oil, 0.006 ml. of 
caraway oil, 0.0018 ml. of coriander oil, 0.02 ml. 
of anise oil, and 0.02 ml. of sassafras oil in 300 
ml. of alcohol. To this solution add 310 ml. of 
propylene glycol, 4.4 Gm. of methenamine, 11.25 
ml. of caramel, and enough purified water to 
make 1000 ml. Mix well, allow the product to 
stand 24 hours, and filter until it is clear. N.F. 
The purpose of the methenamine is to increase 
the solubility of the amobarbital. 

Assay. — A 25-ml. portion of elixir is alkalin- 
ized with sodium hydroxide T.S. and shaken with 
petroleum benzin to remove the flavoring oils; 
after washing the petroleum benzin with water 
it is discarded. The alkaline solution is acidified 
with hydrochloric acid and the amobarbital ex- 
tracted with several portions of ether. The 
washed ether extraction is evaporated to dryness, 
dried at 105°. and weighed. N.F. 

Alcohol Content. — From 27 to 33 per cent, 
by volume, of C2H5OH. N.F. 

The N.F. gives the usual dose as 4 ml. (ap- 
proximately 1 fluidrachm), representing 17.6 mg. 
(approximately l /i grain) of amobarbital. 



Storage. — Preserve "in tight containers." 
N.F. 

AMOBARBITAL TABLETS. U.S.P. 

"Amobarbital Tablets contain not less than 94 
per cent and not more than 106 per cent of the 
labeled amount of C11H18N2O3." U.S.P. 

The tablets are assayed by a modification of 
the procedure described under Barbital Tablets. 

Usual Sizes.— 8, 15, 30, 50, and 100 mg. ( l /s, 
l A, y 2 , Ya and \Vz grains). 

AMOBARBITAL SODIUM. U.S.P. 

[Amobarbitalum Sodicum] 

"Amobarbital Sodium contains not less than 
98.5 per cent of CiiHi7N2Na03, calculated on 
the dried basis." U.S.P. 

Amylobarbitone Sodium, B.P.C. Sodium Isoamylethyl- 
barbiturate. Amytal Sodium (Lilly). 

The sodium derivative of amobarbital may be 
obtained by the interaction of sodium hydroxide 
or sodium carbonate with amobarbital. 

Description. — "Amobarbital Sodium occurs 
as a white, friable, granular powder. It is odorless, 
has a bitter taste, and is hygroscopic. Its solutions 
are alkaline to litmus and to phenolphthalein. 
Amobarbital Sodium is very soluble in water, 
soluble in alcohol, but practically insoluble in 
ether and in chloroform." U.S.P. 

Standards and Tests. — Identification. — (1) 
The amobarbital obtained in the assay melts be- 
tween 156° and 158.5° and responds to the iden- 
tification tests under Amobarbital. (2) The resi- 
due from the ignition of amobarbital sodium ef- 
fervesces with acids and responds to the tests for 
sodium. Loss on drying. — Not over 1 per cent, 
when determined by drying at 105° for 4 hours. 
Heavy metals. — The limit is 30 parts per million. 
Free amobarbital. — Not over 0.5 per cent, the 
amobarbital being extracted with benzene and the 
residue after evaporation of the benzene dried at 
105° for 30 minutes. U.S.P. 

Assay. — A solution of 1 Gm. of amobarbital 
sodium in 15 ml. of water is acidified with hydro- 
chloric acid and the liberated amobarbital is 
extracted with chloroform. The chloroform ex- 
tract is filtered, evaporated to dryness, and the 
residue of amobarbital is dried at 105° for 30 
minutes and weighed. The weight of the residue, 
multiplied by 1.097, represents CnHuNaNaOs. 
U.S.P. 

Uses. — Amobarbital sodium, being soluble in 
water, is the form in which the barbiturate is 
administered parenterally; it may also be given 
orally. For parenteral use the sterile powder, sup- 
plied in ampuls, is used to make the solution and 
this must be prepared immediately before use in 
order to avoid hydrolytic decomposition of the 
barbiturate. A rectal suppository, containing 
200 mg. of amobarbital sodium, is also available. 
The uses are discussed under Amobarbital. 

Dose. — The usual dose is 100 mg. (approxi- 
mately 1^2 grains) once or twice daily by mouth 
or per rectum or, in a 5 or 10 per cent solution, 
intramuscularly or subcutaneousiy. The range of 
dose is 20 to 500 mg. The maximum safe dose 



Part I 



Amodiaquine Hydrochloride 83 



is usually 500 mg. and a total dose of 1 Gm. is 
seldom exceeded in a 24-hour period. When used 
as a preanesthetic sedative as much as 600 mg. 
(approximately 9 grains) may be given. As an 
anticonvulsant in tetanus 800 mg. (approximately 
12 grains) may be required. In emergencies it is 
given intravenously with great caution (not over 
1 ml. per minute of a 5 or 10 per cent solution). 
Storage. — Preserve "in tight containers." 
U.S.P. 

AMOBARBITAL SODIUM CAPSULES. 
U.S.P. 

"Amobarbital Sodium Capsules contain not 
less than 90 per cent and not more than 105 per 
cent of the labeled amount of CnHi7N2Na03." 
c7-SJP- 

Usual Sizes.— 60 and 200 mg. (1 and 3 
grains). 

STERILE AMOBARBITAL SODIUM. 
U.S.P. 

"Sterile Amobarbital Sodium contains not less 
than 98.5 per cent of CuHn^NaOs, calculated 
on the dried basis." U.S.P. 

This is the sterile powder from which injectable 
solutions of amobarbital sodium are prepared by 
addition of water for injection. 

Usual Sizes.— 65, 125, 250, 500, and 750 mg., 
and 1 Gm. 

AMODIAQUINE HYDROCHLORIDE. 
LP. 

Amodiaquini Hydrochloridum 
C20H22ON3Cl.2HCl.2H2O 

Amodiaquine Hydrochloride is 7-chloro-4-(3'- 
diethylaminomethyl - 4' - hydroxyanilino)quinoline 
dihydrochloride clihydrate. It contains not less 
than 98.0 per cent and not more than the equiv- 
alent of 100.0 per cent of C20H22ON3CI.2HCL- 
2H 2 0. LP. 

Camoquin Hydrochloride (Parke, Davis). Miaquin. 
CAM-AQ1. SN 10,751. 

This antimalarial agent is of the 4-aminoquino- 
line type (see article on Antimalarial Agents, in 
Part II) and hence is related to chloroquine. It 
may be prepared from 4,7-dichloroquinoline and 
4-acetamido-a-diethylamino-o-cresol; for details 
of synthesis see Burckhalter et al. (J.A.C.S., 1948, 
70, 1363), also U. S. Patents 2,474,819 and 
2,474,821 (1949). 

Description. — Amodiaquine Hydrochloride oc- 
curs as a yellow, crystalline powder; it is odorless 
and has a better taste. It is soluble in about 22 
parts of water; soluble in alcohol. It melts be- 
tween 154° and 157°, with decomposition. LP. 

Standards and Tests. — Identification. — (1) 
The amodiaquine base obtained in the assay melts 
between 205° and 209°, with decomposition. (2) 
Amodiaquine hydrochloride responds to tests for 
chlorides. Residue on ignition. — Not over 0.2 per 
cent. LP. 

Assay. — About 300 mg. of amodiaquine hy- 
drochloride is dissolved in water, the solution is 
made alkaline with ammonia T.S. and, after the 



mixture has been allowed to stand for not less 
than 30 minutes, the precipitated amodiaquine 
base is collected in a glass filtering crucible, dried 
at 110° for 3 hours, and weighed. LP. 

Uses. — Amodiaquine hydrochloride is a sup- 
pressive antimalarial drug with action similar to 
that of chloroquine (see Chloroquine Phosphate) ; 
it has the advantages of increased effectiveness in 
a single dose and of lesser toxicity. It is rapidly 
absorbed from the gastrointestinal tract. A thera- 
peutic concentration is attained in the blood 
within 1 hour of its ingestion. As with chloroquine, 
the highest concentration of the drug is found in 
the liver. Erythrocytes contain twice the concen- 
tration in blood plasma, which latter is about 190 
micrograms per liter on a dose of 300 mg. daily. 
It remains in the tissues for at least a week after 
a single dose. Less than 5 per cent is excreted in 
the urine. In the form of a 5 per cent aqueous 
solution it may be given intramuscularly with 
only slight induration resulting (Payne et al., Am. 
J. Trop. Med., 1949, 29, 353) or intravenously 
(Payne et al, ibid., 1951, 31, 698). After slow in- 
jection intravenously of 150 or 300 mg. of the 
dihydrochloride only a trivial decrease in blood 
pressure was observed. 

Antimalarial Action. — Amodiaquine is an 
effective suppressive drug (Coggeshall, Am. J. 
Trop. Med. Hyg., 1952, 1, 124) and it rapidly 
controls fever and parasitemia in patients infected 
with P. falciparum, P. vivax, or P. malariae 
(Chaudhuri, Indian Med. Gaz., 1948, 83, 225; 
Singh and Kalyanum, Brit. M. J., 1952, 2, 312; 
Hoekenga, J. A.M. A., 1952, 149, 1369; Love et 
al, Am. J. Med. Sc, 1953, 225, 26). It does not 
affect the gametocytes of P. falciparum or the 
tissue stage of P. vivax, but its tendency to re- 
main in the body for some time delays the relapse 
in P. vivax infestations, particularly in partially 
immune persons. Its efficacy in a single dose and 
the rarity of toxic manifestations are its chief 
advantages. Reports of its value have appeared 
from all parts of the world. Doses have varied 
widely but 10 mg. per Kg. of body weight, or an 
average of 600 mg. for an adult in a single dose, 
seems to be adequate. Several studies indicate 
that a single dose is more effective than the same 
quantity in divided doses over a period of 24 to 
120 hours (Chaudhuri and Chakravarty, Indian 
J. Malariol, 1948, 2, 115; Patel and Mehta, In- 
dian J. Med. Set., 1948, 2, 675; Khan et al, 
Indian Med. Gaz., 1951, 86, 293). A dose of 5 
or of 7.5 mg. per Kg. was reported to be insuffi- 
cient (Simeons and Chhatre, Indian Med. Gaz., 
1947, 82, 255). A single dose of 150 mg. intra- 
muscularly, or 150 to 300 mg. (according to the 
size of the patient and the severity of the symp- 
toms) intravenously controlled the malarial par- 
oxysm (Payne et al, loc. cit.). 

In experimental amebic hepatitis in hamsters, 
Thompson and Reinertson (Am. J. Trop. Med., 
1951, 31, 707) reported that Camoquin and chlo- 
roquine by mouth, and emetine intramuscularly, 
were equally effective, whereas carbarsone, chlo- 
ramphenicol, chlortetracycline, penicillin and di- 
hydrostreptomycin showed little effect. 

Toxicology. — In therapeutically effective 
doses, amodioquine is less toxic than chloroquine 



84 



Amodiaquine Hydrochloride 



Part I 



(Hoekenga, loo. cit.). On a dose of 300 mg. daily, 
which is much larger than is needed for therapy 
or suppression, weakness, insomnia, nausea, vom- 
iting, diarrhea, tenesmus, headache, palpitation, 
and fainting have been reported (Berliner et al., 
J. Clin. Invest., 1948, 27, Suppl., 98). 

Dose. — The dose is 10 mg. of the base per Kg. 
of body weight or 400 to 800 mg. (6 to 12 grains), 
according to the size of the patient, in a single 
dose by mouth to control the malarial paroxysm 
or as a weekly suppressive dose. It will not pre- 
vent relapse in P. vivax malaria as it does not act 
on the tissue stage of the parasite. The dose for 
the infant and child should be calculated on the 
basis of 10 mg. per Kg. of body weight. A dose 
of 150 to 300 mg. may be given slowly intrave- 
nously as a 5 per cent aqueous solution. Camoquin 
hydrochloride is supplied in tablets representing 
200 mg. of the base; the drug is included in 
N.N.R. 

Storage. — Preserve in a well-closed container. 
LP. 

AMPHETAMINE. B.P., LP. 

Amphetaminum 

C6H 5 .CH2.CH(NH 2 ).CH3 

The B.P. defines Amphetamine as (±)-2-ami- 
nopropylbenzene and specifies that it contain not 
less than 98.0 per cent of C9H13N. The LP. indi- 
cates it to be (±)-2-amino-l-phenylpropane and 
requires not less than 97.0 per cent of C9H13N. 
Amphetamine was official in U.S.P. XIV. 

Racemic Amphetamine. l-Phenyl-2-aminopropane. d,l- 
Alphamethylphenethylamine. Racemic Desoxynorephedrine. 
Isomyn. Benzedrine (Smith, Kline & French Labs.). 

Amphetamine may be synthesized in several 
ways. One method starts with phenylacetic acid, 
CeHsCHsCOOH, which is heated with acetic an- 
hydride and sodium acetate to form methyl benzyl 
ketone (phenylacetone), C6H5CH2.CO.CH3; this 
is heated with formamide, HCONH2, yielding the 
formyl derivative of the ketone, CoHsCtb.CH- 
(NHCHO).CH3, which on hydrolysis with acid 
and subsequent alkalinization yields the mixture 
of racemic bases known as amphetamine. Alter- 
natively the methyl benzyl ketone may be con- 
verted to the oxime, which on reduction yields 
amphetamine. 

Description. — Amphetamine is a colorless, 
mobile liquid, having a slight and characteristic 
odor, an acrid taste, and volatilizing slowly at 
ordinary temperatures. It is slightly soluble in 
water; freely soluble in alcohol, in ether, and in 
chloroform; soluble in fixed oils and in volatile 
oils; readily soluble in acids. An aqueous solution 
of amphetamine is alkaline to litmus. The weight 
per ml. of amphetamine, at 20°, is between 0.930 
and 0.935 Gm. B.P., LP. Amphetamine readily 
absorbs carbon dioxide from the air. 

Standards and Tests. — Identification. — (1) 
Amphetamine distils at about 200° with decompo- 
sition. (2) The benzoyl derivative of ampheta- 
mine, twice recrystallized from 50 per cent 
alcohol, melts at about 135°. Water. — No turbid- 
ity is produced on dissolving 1 ml. of ampheta- 
mine in 10 ml. of anhydrous liquid paraffin. 



Non-volatile matter. — Not over 2.5 mg. of residue 
remains when 500 mg. of amphetamine is heated 
on a water bath for 1 hour and dried to constant 
weight at 105°. Residue on ignition. — Not over 
0.1 per cent. B.P., LP. 

Assay. — The B.P. directs that 250 mg. of 
amphetamine be dissolved in 25 ml. of 0.1 N 
hydrochloric acid and the excess of acid titrated 
with 0.1 N sodium hydroxide, using methyl red 
as indicator. Each ml. of 0.1 N acid is equiva- 
lent to 13.52 mg. of C9H13N. The LP. directs 
solution of about 250 mg. of amphetamine in 
10 ml. of alcohol and direct titration with 0.1 N 
hydrochloric acid, using methyl red as indicator. 

Uses. — Amphetamine and its salts belong to 
the general class of sympathomimetic agents (see 
monograph on this subject in Part II). A distinc- 
tion is made between the racemic preparation, 
which is referred to simply as amphetamine, and 
the dextrorotatory isomer, called d-amphetamine 
or dextro-amphetamine (Dexedrine, Smith, Kline 
& French). The actions of amphetamine are 
similar to those of ephedrine and methampheta- 
mine. 

Amphetamine and its carbonate, being volatile, 
were formerly used in inhalers to permit appli- 
cation of the vapor to nasal mucosa, thereby 
effecting shrinkage of swollen and congested 
nasal structures in head colds, sinusitis, vaso- 
motor rhinitis, and hay fever. One or two inhala- 
tions through each nostril, at hourly intervals, 
was recommended. Simpson and Simon (Am. J. 
Pharm., 1937, 109, 343) found that ordinarily 
the patient would inhale into the lungs approxi- 
mately 0.05 mg. per inhalation, which seemed un- 
likely to render any constitutional effect. Swine- 
ford (/. Allergy, 1938, 9, 572) found, however, 
that it was possible by very deep inhalations to 
carry sufficient amphetamine into the bronchi to 
cause blanching of the mucosa. Although unto- 
ward effects were infrequent with proper use, the 
convenience and simplicity of the inhaler facili- 
tated excessive dosage with resultant undesirable 
symptoms, especially in susceptible individuals. 
Such overdosage paralyzed ciliary action of the 
respiratory mucous membranes, caused abnormal 
dryness, and actually aggravated rather than cor- 
rected swelling and congestion, with the possi- 
bility of development of atrophic rhinitis (Kully, 
J.A.M.A., 1945, 127, 307). Restlessness and in- 
somnia were the most frequent untoward effects. 
Inhalations were contraindicated in patients with 
cardiovascular disease or marked sensitivity to the 
drug. Inhalers containing amphetamine were 
withdrawn from the market in the United States 
because of their misuse to produce a "Benzedrine 
jag" by soaking the medicated fabric inside the 
inhaler with water or beverage and drinking the 
solution. Propylhexedrine (Benzedrex) replaced 
the amphetamine (Benzedrine) in these inhalers. 
Oil solutions of amphetamine are sometimes used 
for topical application. 

Amphetamine sulfate is administered orally in 
the treatment of narcolepsy, postencephalitic 
parkinsonism, mental depression, alcoholism, 
obesity and spastic conditions of the gastrointes- 
tinal tract. Its pharmacology was reviewed by 
Ivy and Krasno (War Med., 1941, 1, 15). 



Part I 



Amphetamine 85 



Cardiorespiratory Action. — In sufficient dose, 
amphetamine causes a marked rise in the blood 
pressure which comes on rather slowly and lasts 
for a prolonged time. Beyer (/. Pharmacol., 1939, 
66, 318) found that 33 mg. of the drug caused, 
in humans, an average rise in the blood pressure 
of about 25 mm. of mercury which lasted for 
more than seven hours. According to Tainter et al. 
(J. Pharmacol., 1936, 57, 152; 1938, 64, 190; 
1939, 66, 146), it does not dilate the bronchi but 
it has a depressant effect on the muscles of the 
gastrointestinal tract. Beyer showed that in man 
it causes a distinct rise in the metabolic rate 
which lasts for more than nine hours. In many 
persons it causes a loss of appetite, perhaps from 
the delayed emptying of the stomach (Beyer and 
Meek, Ann. Int. Med., 1939, 63, 752). The most 
valuable property of this drug is its stimulating 
effect on cerebral, respiratory and vasomotor 
activity which exceeds that of any other drug of 
the sympathomimetic group (Warren and Werner, 
/. Pharmacol., 1945, 85, 119). Handley and 
Ensberg (Anesth., 1945, 6, 561) found it to be 
the most effective and the most rapidly acting 
stimulant to antagonize respiratory depression due 
to morphine; the other drugs studied were nik- 
ethamide, ephedrine, pentylenetetrazol, and caf- 
feine. 

Central Nervous System Effects. — The 
effects of amphetamine and its salts on the cere- 
brum have led to its widespread use in the treat- 
ment of conditions of mental depression, exhaus- 
tion and even aberrations. Grant (Air Force, 1944, 
March) described the use of amphetamine to 
avoid sleepiness in aviators and this use of the 
drug by ground troops was discussed in Circular 
Letter No. 58, issued by the United States War 
Department, February 23, 1943. For mental weari- 
ness, 5 mg. every 3 hours was advised; for physi- 
cal fatigue, 10 mg. every 6 hours. The total dose 
should not exceed 30 mg. per week and adequate 
rest must be obtained at the end of each period 
of overexertion. It is valuable in the treatment 
not only of acute alcoholism but also of the alco- 
holic psychoses (Reifenstein and Davidoff, 
J. A.M. A., 1938, 10, 1811; Miller, ibid., 1942, 
120, 271). The effect of amphetamine on higher 
nervous activity in the human has been compared 
with that of alcohol by Finkelstein et al. {Bull. 
Johns Hopkins Hosp., 1945, 76, 61). Ampheta- 
mine improved the response to conditioned and 
unconditioned stimuli, whereas alcohol decreased 
the response. Amphetamine has been employed 
with more or less temporary benefit in the treat- 
ment of various depressive insanities and is often 
of service in narcolepsy (Prinzmetal et al., 
J.A.M.A., 1935, 105, 25) and catalepsy. Combined 
with amobarbital it is claimed to moderate ex- 
tremes of mood and to give the depressed patient 
a more normal outlook and behavior (Grahn, 
American Practitioner, 1950, 1, 795). In post- 
encephalitic parkinsonism it causes not only im- 
provement in the mental attitude but also lessens 
rigidity and tremor. It is most effective in combi- 
nation with stramonium or scopolamine (Mat- 
thews, Am. J. Med. Sc, 1938, 195, 448). Myerson 
and Loman (Arch. Neurol. Psychiat., 1942, 48, 



823) reported successful treatment of spasmodic 
torticollis with amphetamine sulfate. 

Amphetamine sulfate has been used effectively 
in the treatment of barbiturate poisoning (Myer- 
son et al., New Eng. J. Med., 1939, 221, 1015; 
Kornblau, Anesth. & Analg., 1948, 27, 116; 
Nabarro, Brit. M. J., 1950, 2, 924; Dick, Am. J. 
Med. Sc, 1952, 224, 281); in the depression 
associated with the withdrawal of morphine from 
addicts (Duckworth, Brit. M. J., 1940, 2, 628); 
for the exhaustion and lassitude of roentgen ill- 
ness (Jenkinson and Brown, Am. J. Roentgen., 
1944, 51, 496); in hypotension (Peoples and 
Guttmann, Lancet, 1936, 1, 1107); in various 
combinations, as with phenobarbital, in the treat- 
ment of petit mal epilepsy (Livingston and Kajidi, 
J.A.M.A., 1945, 129, 1071); with belladonna and 
a barbiturate in seasickness (Hill, Brit. M. J., 
1937, 2, 1109). Burrill et al. (J. Dent. Research, 
1944, 23, 337) found that amphetamine sulfate 
increased the analgesic effect of acetophenetidin. 
Hindes (Ind. Med., 1946, 15, 262) reported bene- 
fit in 96 per cent of dysmenorrhea cases. 

Antispasmodic Uses. — Amphetamine sulfate 
has also been used to lessen spasm of the alimen- 
tary tract, gall bladder or ureters to facilitate 
roentgenography of the intestinal tract. Rosen- 
berg et al. (J. A.M. A., 1938, 110, 1944) found 
that spastic colon was not relieved. Indeed, its 
use as an intestinal antispasmodic agent is quite 
limited, being overshadowed by its effects on the 
cardiovascular and the central nervous system. 

Use in Obesity. — Amphetamine sulfate is 
employed for the reduction of body weight (Al- 
brecht, Ann. Int. Med., 1944, 21, 983; Pelner, 
ibid., 1945, 22, 201), its effect being due probably 
to a combination of increased metabolism and 
decreased appetite (see Harris et al., J. A.M. A., 
1947, 134, 1468; Goetzl and Stone, Gastro- 
enterology, 1948, 10, 1948; Roberts, Ann. Int. 
Med., 1951, 34, 1324; Freed and Mizel, ibid., 
1952, 36, 1492). 

Toxicology. — The widespread use of ampheta- 
mine sulfate to counteract depression, the result 
of fatigue or alcoholism, is greatly to be depre- 
cated for three reasons: (1) the tendency toward 
habit formation, (2) the almost certain rise in 
blood pressure, and (3) the fact that under some 
circumstances not understood it may produce 
dangerous circulatory collapse. Smith (J. A.M. A., 
1939, 113, 1022) reported a case of collapse 
terminating fatally. Apfelberg (ibid., 1938, 110, 
575), Hertzog and Karlstrom (ibid., 1943, 121, 
256), and Gericke (ibid., 1945, 128, 1098) also 
reported cases of poisoning. However, the inci- 
dence of untoward effects has been surprisingly 
low and the symptoms of headache, restlessness, 
insomnia, irritability, palpitation and disturbance 
in bowel habit have usually been mild and have 
disappeared rapidly on discontinuance of the drug 
(Pelner, N. Y. State J. Med., 1944, 44, 2596). 
Daily doses as large as 30 to 50 mg. have been 
long continued without ill effects (Myerson, Am. 
J. Med. Sc, 1940, 199, 729) and Bakst (U. S. 
Nav. M. Bull., 1944, 43, 1228) reported absence 
of untoward effects or withdrawal manifestations 
after daily use during nine years. Shorvon (Brit. 
M. /., 1945, 2, 285) discussed the problem of 



86 Amphetamine 



Part I 



addiction in psychopathic patients; withdrawal of 
the drug from a patient accustomed to consuming 
daily for many months twenty-five to thirty 5 mg. 
tablets indicated mental but not physical depend- 
ence. Clinical experience has been that certain 
types of psychopaths can well tolerate and benefit 
from large doses of amphetamine. In general, 
untoward effects have been due to overdosage or 
improper dosage. El 

Dose. — Amphetamine base is used only by 
inhalation (see above) ; its salts are used orally or 
parenterally. The usual dose of amphetamine sul- 
fate is 10 mg. (approximately % grain) twice a day 
by mouth, with a range of 2.5 to 10 mg. The 
maximum safe dose is usually 20 mg. and the 
maximum dose in 24 hours should seldom exceed 
100 mg. Because of variation in individual sus- 
ceptibility, treatment with amphetamine sulfate 
should be started with a test dose of 2.5 to 5 mg. 
(approximately }4s to V12 grain). To avoid in- 
somnia, the drug is best given during the morn- 
ing and preferably not later than midafternoon. 
The average doses for its common uses are as fol- 
lows: depressive states, 5 to 10 mg. twice daily; 
alcoholism, 5 to 15 mg. twice daily; postencepha- 
litic parkinsonism, 10 to 20 mg. twice daily; 
narcolepsy, 10 to 40 mg. two or three times daily 
as required; obesity, 2.5 to 5 mg. twice daily 
about one-half hour before meals. In barbiturate 
poisoning, the initial dose is 20 to 50 mg. intra- 
venously in a 2 per cent solution; subsequently 
50 to 100 mg. may be given intramuscularly, every 
hour if necessary, to counteract the hypnosis and 
depression of the central nervous system. 

AMPHETAMINE PHOSPHATE. N.F. 

Racemic Amphetamine Phosphate, rf/-Monobasic 
Amphetamine Phosphate, d/-Amphetaminium Phosphate 

C9H13N.H3PO4 

"Amphetamine Phosphate, dried at 105° for 2 
hours, contains not less than 98 per cent of 
C9H13N.H3PO4." N.F. 

Profetamine Phosphate (Clark & Clark) ; Raphetamine 
Phosphate (Strasenburgh) . 

This salt differs from amphetamine sulfate in 
being a salt of phosphoric acid in which one of 
the three hydrogen atoms of the latter is neu- 
tralized by amphetamine base. 

Description. — "Amphetamine Phosphate oc- 
curs as a white, odorless, crystalline powder. It 
has a bitter taste. Amphetamine Phosphate i» 
freely soluble in water, and slightly soluble in alco- 
hol. It is practically insoluble in benzene, in chloro- 
form, and in ether. The pH of a solution of 
Amphetamine Phosphate (1 in 20) is between 
4 and 5." N.F. 

The standards, tests and assay are identical 
with those for amphetamine sulfate, except for 
the difference in the identification of the cation; 
also, the residue on ignition of amphetamine phos- 
phate is 0.1 per cent. 

Uses. — Amphetamine phosphate is used for 
the same purposes as amphetamine sulfate. Be- 
cause of the lower content of amphetamine base 
in the phosphate, as compared with the sulfate, it 
may be calculated that 12.6 mg. of the phosphate 
is equivalent to 10 mg. of the sulfate, so that 



doses of amphetamine phosphate would have to 
be approximately 25 per cent greater than those 
of amphetamine sulfate for equivalent effect. For 
most purposes, however, amphetamine phosphate 
is actually used in the same dose as amphetamine 
sulfate. As an analeptic amphetamine phosphate 
is administered intravenously or intramuscularly 
in doses of 20 to 50 mg. every 30 to 60 minutes 
until consciousness is restored; the solution em- 
ployed commonly contains 10 mg. per ml. and is 
preserved with 0.5 per cent chlorobutanol. The 
N.F. gives the usual dose as 5 mg. 

Storage. — Preserve "in well-closed contain- 
ers." N.F. 

AMPHETAMINE PHOSPHATE 
INJECTION. N.F. 

"Amphetamine Phosphate Injection is a sterile 
solution of amphetamine phosphate in water for 
injection. It contains not less than 95 per cent 
and not more than 105 per cent of the labeled 
amount of C9H13N.H3PO4." N.F. 

Storage. — Preserve "in single-dose or mul- 
tiple-dose containers, preferably of Type I glass." 
N.F. 

Usual Size. — 100 mg. in 10 ml. 

AMPHETAMINE PHOSPHATE 
TABLETS. N.F. 

"Amphetamine Phosphate Tablets contain not 
less than 90 per cent and not more than 110 per 
cent of the labeled amount of C9H13N.H3PO4." 
N.F. 

Usual Size. — 5 mg. (approximately Vn grain). 

DIBASIC AMPHETAMINE 
PHOSPHATE. N.F. 

Racemic Dibasic Amphetamine Phosphate, rf/Dibasic 

Amphetamine Phosphate, ^'/-Dibasic Amphetaminium 

Phosphate 

(C9Hi 3 N) 2 .H 3 P04 

"Dibasic Amphetamine Phosphate, dried at 
105° for 2 hours, contains not less than 98 per 
cent of (C9H 13 N)2.H 3 P04." N.F. 

This salt differs from amphetamine phosphate 
in that two of the hydrogen atoms of phosphoric 
acid are neutralized by amphetamine base. 

Description. — "Dibasic Amphetamine Phos- 
phate occurs as a white, odorless, crystalline pow- 
der. It has a slightly bitter taste. One Gm. of 
Dibasic Amphetamine Phosphate dissolves in 
about 20 ml. of water, and in about 650 ml. of 
alcohol. It is insoluble in ether. The pH of a solu- 
tion of Dibasic Amphetamine Phosphate (1 in 
20) is between 7 and 8.5." N.F. 

Uses. — This salt differs from amphetamine 
phosphate in containing approximately 25 per 
cent more of amphetamine base and thus it is 
equivalent to amphetamine sulfate when equal 
weights of the two are compared. Dibasic am- 
phetamine phosphate is neutral in aqueous solu- 
tion, while the monobasic phosphate is acid; this 
difference, however, is of no significance in the 
use of the two salts. The dose of dibasic ampheta- 
mine phosphate is exactly the same as that of 
amphetamine sulfate. The N.F. gives the usual 
dose as 5 mg. 



Part I 



Amphetamine Sulfate 87 



Storage. — Preserve "in well-closed containers." 
N.F. 

DIBASIC AMPHETAMINE 
PHOSPHATE TABLETS. N.F. 

"Dibasic Amphetamine Phosphate Tablets con- 
tain not less than 90 per cent and not more 
than 110 per cent of the labeled amount of 
(C9Hi 3 N) 2 .H 3 P04." N.F. 

Usual Size. — 5 mg. (approximately Yi2 grain). 

DEXTRO-AMPHETAMINE 
PHOSPHATE. N.F. 

Monobasic Dextro-amphetamine Phosphate, Dextro- 
amphetaminium Phosphate 

C9H13N.H3PO4 

"Dextro-amphetamine Phosphate, dried at 105° 
for 2 hours, contains not less than 98.5 per cent of 
C9H13N.H3PO4." N.F. 

This salt has the same relationship to ampheta- 
mine phosphate as dextro-amphetamine sulfate 
has to amphetamine sulfate. 

Description. — "Dextro-amphetamine Phos- 
phate occurs as a white, odorless, crystalline pow- 
der. It has a bitter taste. One Gm. of Dextro- 
amphetamine Phosphate dissolves in 20 ml. of 
water. It is slightly soluble in alcohol and is prac- 
tically insoluble in benzene, in chloroform, and in 
ether. The pH of a solution of Dextro-ampheta- 
mine Phosphate (1 in 10) is between 4 and 5." 
N.F. 

Uses. — Dextro-amphetamine phosphate has the 
same actions and uses as amphetamine sulfate 
but, as with the dextro form of amphetamine 
sulfate, the dextro isomer of amphetamine phos- 
phate is about twice as active in its central stimu- 
lant effects as the racemic form of amphetamine 
phosphate. Accordingly the usual dose of the dex- 
tro isomer should be about half that of racemic 
monobasic amphetamine phosphate; however, the 
N.F. gives the usual dose as 5 mg. 

Storage. — Preserve "in well-closed containers." 
N.F. 

DEXTRO-AMPHETAMINE 
PHOSPHATE TABLETS. N.F. 

"Dextro-amphetamine Phosphate Tablets con- 
tain not less than 90 per cent and not more 
than 110 per cent of the labeled amount of 
C9H13N.H3PO4." N.F. 

Usual Size. — 5 mg. 

DIBASIC DEXTRO-AMPHETAMINE 
PHOSPHATE. N.F. 

Dibasic Dextro-amphetaminium Phosphate 

(C9Hi 3 N)2.H 3 P04 

"Dibasic Dextro-amphetamine Phosphate, dried 
at 105° for 2 hours, contains not less than 98 per 
cent of (C9Hi 3 N) 2 .H 3 P04." N.F. 

This salt corresponds to the dextro isomer of 
amphetamine sulfate in containing, by a coinci- 
dence of molecular weights, the same proportion 
of amphetamine. It differs from dextro-ampheta- 
mine phosphate in that two of the hydrogen 
atoms of phosphoric acid are neutralized by am- 



phetamine, thereby making the salt less acid than 
dextro-amphetamine phosphate. 

Description. — "Dibasic Dextro-amphetamine 
Phosphate occurs as a white, odorless, crystalline 
powder. It has a slightly bitter taste. One Gm. of 
Dibasic Dextro-amphetamine Phosphate dissolves 
in about 20 ml. of water, and in about 650 ml. of 
alcohol. It is insoluble in ether. The pH of a solu- 
tion of Dibasic Dextro-amphetamine Phosphate 
(1 in 20) is between 6.0 and 7.5." N.F. 

Uses. — The uses of this dextro isomer are 
qualitatively the same as amphetamine sulfate; 
the dose is theoretically and actually the same as 
for dextro-amphetamine sulfate, since both dextro 
salts contain the same proportion of active base. 
The N.F. gives the usual dose as 5 mg. 

Storage. — Preserve "in well-closed containers." 
N.F. 

DIBASIC DEXTRO-AMPHETAMINE 
PHOSPHATE TABLETS. N.F. 

"Dibasic Dextro-amphetamine Phosphate Tab- 
lets contain not less than 90 per cent and not 
more than 110 per cent of the labeled amount of 
(C 9 Hi3N) 2 .H 3 P04." N.F. 

Usual Size. — 5 mg. 

AMPHETAMINE SULFATE. 
U.S.P., B.P., LP. 

Amphetaminium Sulfate, d/-l-Phenyl-2-aminopropane 
Sulfate, [Amphetaminae Sulfas] 




ch,chch, so; 

NH 3 

"Amphetamine Sulfate, dried at 105° for 2 
hours, contains not less than 98 per cent and not 
more than 100.5 per cent of (C9Hi3N)2.H.2S04." 
U.S. P. The B.P. defines Amphetamine Sulphate as 
(±)-2-aminopropylbenzene sulfate, and requires 
not less than 99.0 per cent of (CgHi3N)2.H2S04, 
calculated with reference to the substance dried 
to constant weight at 105°. The LP. defines it as 
(±)-2-amino-l-phenylpropane sulfate, and re- 
quires not less than 98.0 per cent of (CgHi3N)2.- 
H2SO4, the substance not being dried prior to 
assay. 

B.P. Amphetamine Sulphate. LP. Amphetamini Sulfas. 
Racemic Amphetamine Sulfate. d/-a-Methylphenethylamine 
Sulfate. Benzedrine Sulfate (Smith, Kline & French Labs.). 

The B.P. states that this salt may be prepared 
by neutralizing an alcoholic solution of ampheta- 
mine base with sulfuric acid. 

Description. — "Amphetamine Sulfate occurs 
as a white, odorless, crystalline powder. It has a 
slightly bitter taste. Its solutions are acid to 
litmus, having a pH of 5 to 6. One Gm. of 
Amphetamine Sulfate dissolves in about 9 ml. of 
water, and in about 500 ml. of alcohol. It is in- 
soluble in ether." U.S.P. 

Standards and Tests. — Identification. — (1) 
The benzoyl derivative of amphetamine melts be- 
tween 131° and 135°. (2) A solution of ampheta- 
mine sulfate responds to tests for sulfate. Water. 
— Not over 1 per cent when dried at 105° for 
2 hours. Residue on ignition. — Not over 0.2 per 



88 Amphetamine Sulfate 



Part I 



cent. Dextroamphetamine. — A 1 in SO solution 
of amphetamine sulfate is optically inactive. 
U.S.P. 

Assay. — A sample of 300 mg. of dried am- 
phetamine sulfate is dissolved in water, made 
alkaline with sodium hydroxide, and the ampheta- 
mine base extracted with ether. The ether is 
evaporated to a volume of about 10 ml., 20 ml. 
of 0.1 N sulfuric acid is added and. after evapo- 
ration of the remainder of the ether, the excess 
of acid is titrated with 0.1 A* sodium hydroxide, 
using methyl red T.S. as indicator. Each ml. of 
0.1 A 7 sulfuric acid represents 18.43 mg. of 
(C 9 Hi3N)2.H 2 S04. U.S.P. 

For uses and dose of amphetamine sulfate see 
under Amphetamine, [v] 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

AMPHETAMINE SULFATE 
TABLETS. U.S.P. (LP.) 

"Amphetamine Sulfate Tablets contain not less 
ihan 90 per cent and not more than 110 per cent 
of the labeled amount of (C9Hi3N)2.H2S04." 
U.S.P. The corresponding LP. limits are 92.0 to 
108.0 per cent. 

LP. Tablets of Amphetamine Sulfate; Compressi Am- 
pbetamini Sulfatis. 

Usual Sizes. — 5 and 10 mg. 

DEXTRO AMPHETAMINE 
SULFATE. U.S.P. 

d-Amphetaminium Sulfate, d-l-Phenyl-2-amino- 
propane Sulfate 

"Dextro Amphetamine Sulfate, the dextrorota- 
tory isomer of amphetamine sulfate, dried at 105° 
for 2 hours, contains not less than 98 per cent and 
not more than 100.5 per cent of (C9Hi3N)2.- 
H2SO4." U.S.P. 

Dexedrine Sulfate (.Smith, Kline & French Labs.). 

Dextro amphetamine sulfate is obtained by 
resolution of the racemic variety, which is official 
as Amphetamine Sulfate. 

Description. — "Dextro Amphetamine Sulfate 
occurs as a white, odorless, crystalline powder. 
Its 1 in 20 solution is acid to litmus, having a pH 
of 5 to 6.3. One Gm. of Dextro Amphetamine 
Sulfate dissolves in about 10 ml. of water and in 
about 800 ml. of alcohol. It is insoluble in ether." 
U.S.P. 

Standards and Tests. — Identification. — (1) 
The benzoyl derivative melts between 155° and 
158°. (2) A 1 in 10 solution of dextro amphet- 
amine sulfate responds to tests for sulfate. Spe- 
cific rotation. — Not less than +20° and not more 
than +23. 5°, when determined in a solution con- 
taining 400 mg. of dried dextro amphetamine sul- 
fate in each 10 ml. Loss on drying. — Not over 
1 per cent, when dried at 105° for 2 hours. Resi- 
due on ignition. — Not over 0.1 per cent. U.S.P. 

Assay. — The assay is performed as described 
under Amphetamine Sulfate. U.S.P. 

Uses. — The dextrorotatory form of amphet- 
amine was observed bv Prinzmetal and Alles 
(Proc. S. Exp. Bio. Med., 1939, 42, 206) to have 
a substantially greater central nervous stimulating 



effect than the racemic form; also, the levorota- 
tory form was found to be relatively devoid of 
this euphoriant action. Otherwise the actions of 
the optically active and racemic forms of the 
compound are pharmacodynamically similar. The 
general clinical pharmacology of amphetamine 
has been discussed in the monograph on Amphet- 
amine; for further information see Reifenstein 
and Davidoff (N. Y. State J. Med., 1939, 39, 42). 
Confirming the initial observations of Prinzmetal 
and Alles, Davidoff (Med. Rec, 1943, 156, 422) 
reported racemic amphetamine to be distinctly 
weaker in its stimulation of motor and intellectual 
function than either d-amphetamine or desoxy- 
ephedrine (methamphetamine). Similarly, Novelli 
and Tainter (/. Pharmacol., 1943, 77, 325) re- 
ported that dextro amphetamine was at least twice 
as active as the racemic form in its effects on the 
motor activity of rats. This effect on the sensorium 
and motor phenomena is attributable to an inher- 
ent activity of the compound which is unique, 
for usually the levo-form of biologically active 
agents having one asymmetric carbon atom is 
more active than the dextro form. 

Beyer and Skinner (ibid., 1940, 68, 419) stud- 
ied the detoxication and excretion of racemic 
amphetamine and its optically active forms in 
man. They found essentially no difference in the 
absorption and excretion of the three forms, al- 
though the greater effect of the dextro form on 
the sensorium was quite evident. Thus, up to 64 
per cent of either active form of amphetamine 
was excreted during a period of 24 hours. 

As a generalization, dextro amphetamine tends 
to be used in place of the racemic form in those 
conditions where stimulation of the sensorium is 
indicated, as in certain depressive states, in post- 
encephalitic parkinsonism, and in narcolepsy. In 
a study of comparative therapeutic effects of the 
two forms on humans, Freed (West. J. Surg. 
Obst. Gyn., 1949, 57, 67) found the racemic salt 
to be equal, in appetite-curbing effect, to the 
dextro salt when the latter is used in half the 
dose of the former. He received the clinical im- 
pression that the individual who requires large 
doses of most drugs for a therapeutic effect re- 
sponds more satisfactorily to racemic amphet- 
amine sulfate than to the dextro isomer; the high- 
strung, hypersensitive individual who is prone to 
drug intolerance and who responds to small doses 
of drugs in general seems to prefer the dextro 
isomer. In anhedonic individuals the levo form 
of amphetamine, which is present in the racemic 
drug, produces through its stronger adrenergic 
action a satiation to food at lower dosage levels; 
the hypersensitive individual, on the other hand, 
does not tolerate too well the adrenergic effect of 
the levo isomer and therefore prefers dextro 
amphetamine sulfate. 

Toxicology. — The undesirable effects of the 
drug following overdosage are excessive excite- 
ment, loquaciousness, headache and insomnia, as 
observed also with racemic amphetamine. Since 
the drug is slowly excreted and metabolized these 
effects may persist for 24 to 48 hours when the 
dose is excessive. According to Freed (loc. cit.) 
there is considerably less incidence of side reac- 
tions with dextro amphetamine sulfate than with 



Part I 



Amyl Nitrite 89 



the racemic salt. Since the peripheral vascular 
action of the dextro and racemic salts is believed 
to be quantitatively the same, it is apparent that 
the lower dosage required in the case of the dextro 
compound is less likely to elicit peripheral vascu- 
lar complications. Dextro amphetamine sulfate is 
usually not indicated in cases of severe hyper- 
tension, angina pectoris, hyperthyroidism, and 
Raynaud's disease. 

Dose. — The usual adult dose of dextro amphet- 
amine sulfate in simple depressed states, obesity, 
alcoholism, hyperemesis gravidarum, or drowsi- 
ness is 5 mg. twice a day, with a range of dose 
of 2.5 to 5 mg. The last dose should precede the 
anticipated bedtime by at least 4 hours; other- 
wise, the stimulating effect of the drug will inter- 
fere with sleep, in which case it may be necessary 
to counteract the effect with barbiturate hypnotics. 
The dose for control of narcolepsy or the depres- 
sion of parkinsonism may be 25 mg. a day or 
more, symptomatically. The maximum safe dose 
in 24 hours seldom exceeds 50 mg. Dexedrine 
Sulfate Spanstdes contain 15 mg. of the dextro 
salt in the form of tiny pellets, of which there 
are over a hundred in each capsule, having vary- 
ing disintegration times so as to release the drug 
uniformly over a period of 8 to 10 hours; for use 
in weight reduction one such capsule, taken in 
the morning, curbs appetite throughout the day. 

Storage. — Preserve "in well-closed containers." 
U.S.P. 

DEXTRO AMPHETAMINE SULFATE 
TABLETS. U.S.P. 

"Dextro Amphetamine Sulfate Tablets contain 
not less than 90 per cent and not more than 110 
per cent of the labeled amount of (C,9Hi3N)2.H2- 
S0 4 ." U.S.P. 

Usual Sizes. — 5 and 10 mg. 

AMYL NITRITE. U.S.P., B.P., LP. 

Isoamyl Nitrite, [Amylis Nitris] 

CH 3 .CH(CH 3 ) .CH2.CH2.ONO 

"Amyl Nitrite contains not less than 90 per 
cent of C5H11NO2. Caution. — Amyl Nitrite is 
very flammable. Do not use where it may be 
ignited." U.S.P. 

The B.P. states that Amyl Nitrite consists 
chiefly of the nitrites of 3-methylbutanol, (013)2- 
CH.CH2.CH2.OH, and 2-methylbutanol, (C2H5) 
(CH3)CH.CH2.0H; it is required to contain not 
less than 90.0 per cent w/w of nitrites, calculated 
as CsHuCteN. The LP. indicates it to be a mix- 
ture of the nitrite of 3-methylbutanol- 1 with a 
small quantity of the nitrite of 2-methylbutanol-l 
and other nitrites of the homologous series; the 
purity rubric is the same as that of the U.S.P. 
and B.P. 

Araylium Nitrosum; Nitris Amylicus. Ft. Azotite d'amyle. 
Ger. Amylnitrit; Salpetrigsaureamylester. It. Nitrito 
d'amile; Nitrito d'isoamile. Sp. Nitrito de amilo; Ester 
isoamilnitroso. 

This substance, discovered by Balard in 1844, 
is the product of esterifi cation of amyl alcohol 
and nitrous acid. A convenient method for pre- 
paring the ester by the interaction of amyl alcohol, 



sulfuric acid and sodium nitrite is described by 
Noyes (J.A.C.S., 1933, 55, 3888). Other methods 
of preparation are described in the U.S.D., 20th 
ed., p. 140. 

The amyl alcohol used in the preparation of 
amyl nitrite is frequently a mixture of isomeric 
alcohols; as a result, the product may likewise 
be a mixture of two or more isomers. Usually, 
it consists chiefly of isoamyl nitrite, 

CH3.CH ( CH 3 ) .CH2.CH2.ONO 

with smaller proportions of optically active, sec- 
ondary and amyl nitrite, CH3.CH2.CH(CH3).- 
CH2.ONO. Read et al. {Chinese J. Physiol, 1933, 
7, 253) made comparative physiological studies 
of the effects of the various isomeric amyl nitrites; 
they found that all act qualitatively alike but be- 
lieve that the tertiary amyl nitrite is the most 
valuable from the standpoint of practical thera- 
peutics. 

Description. — "Amyl Nitrite is a clear, yel- 
lowish liquid, having a peculiar, ethereal, fruity 
odor. It is volatile even at low temperatures and 
is flammable. Amyl Nitrite is almost insoluble in 
water, but is miscible with alcohol and with ether. 
The specific gravity of Amyl Nitrite is not less 
than 0.865 and not more than 0.875." U.S.P. 

Standards and Tests. — Identification. — (1) 
Amyl valerate, recognizable by its odor, is pro- 
duced when a mixture of 2 ml. of sulfuric acid, 2 
drops of amyl nitrite and 2 drops of water is di- 
luted with water. (2) A greenish brown color is 
produced on adding a few drop of amyl nitrite to 
a mixture of 1 ml. of ferrous sulfate T.S. and 5 
ml. of diluted hydrochloric acid. Acidity. — The 
red tint of a mixture of 1 ml. of normal sodium 
hydroxide, 10 ml. of water and 1 drop of phenol- 
phthalein T.S. is not discharged by 5 ml. of amyl 
nitrite when the glass-stoppered cylinder used as 
a container is inverted three times. Aldehyde. — 
No brown or black color is developed on mixing, 
successively, 1.5 ml. of silver nitrate T.S., 1.5 ml. 
of aldehyde-free alcohol, enough ammonia T.S. to 
redissolve the precipitate which forms, and 1 ml. 
of amyl nitrite, the mixture being heated gently 
for 1 minute. U.S.P. 

The B.P. specifies that not less than 85 per cent 
shall distil between 90° and 100°. The residue on 
evaporation is not more than 0.01 per cent w/v. 
A test for aldehyde, based on the color produced 
with sodium hydroxide, is also given. 

Assay. — A 3-ml. sample of amyl nitrite is 
weighed in alcohol and the solution diluted to 100 
ml. A 10-ml. portion of this solution is assayed 
gasometrically, by the method described under 
Ethyl Nitrite Spirit. U.S.P. 

The B.P. assay is practically the same as that 
of the U.S.P. The LP. assay is based on the re- 
duction of potassium chlorate by the nitrite to 
potassium chloride, the amount of the latter being 
determined by precipitation with a measured ex- 
cess of 0.1 A7 silver nitrate, followed by titration 
of the excess silver nitrate with 0.1 N ammonium 
thiocyanate, with the silver chloride being re- 
moved by filtration. Since three molecules of amyl 
nitrite are required to reduce one molecule of 
potassium chlorate to chloride, the equivalent 
weight of amyl nitrite is three times its molecular 



90 Amyl Nitrite 



Part I 



weight. Each ml. of 0.1 N silver nitrate repre- 
sents 35.1 mg. of C5H11O2N. LP. 

Uses. — Physiologically, amyl nitrite acts like 
sodium nitrite (g. v.), except that it is much 
quicker and more evanescent, its effect appearing 
in about 30 seconds and lasting for only about 3 
minutes. Amyl nitrite is used in medicine for 
three purposes: To relax spasms in the arteries, 
to control convulsions, and for the relief of the 
asthmatic paroxysm. It is of service only where 
an immediate, transient effect is desired. 

Cardiac. — In angina pectoris it improves cir- 
culation in the coronary arteries, even though a 
drop in blood pressure occurs. Since the duration 
of angina attacks is less than 3 minutes in the 
majority of cases (Riseman and Brown, New 
Eng. J. Med., 1937, 217, 470) only the rapidly 
acting substances, amyl nitrite or nitroglycerin, 
are effective. The pain due to demonstrable (elec- 
trocardiogram or gross pathology) myocardial 
infarction is usually not benefited by nitrites; 
since such patients often manifest peripheral cir- 
culatory collapse, nitrites must be employed with 
great caution. Goldberger {Am. Heart J., 1945, 
30, 60) made electrocardiograms following amyl 
nitrite inhalation by patients with hypertension 
and enlargement of the heart; most of these pa- 
tients showed a change of the T wave from nega- 
tive to positive for 3 to 4 minutes. Gross {Am. 
Heart J ., 1945, 30, 19) reported on the use of 
the time between the first inhalation of amyl 
nitrite and the appearance of a definite heat sensa- 
tion in the face as a measurement of lung-to-face 
circulation time; in normal persons the time 
ranged from 14 to 25 seconds; in congestive heart 
failure the time varied from 31 to 54 seconds; in 
emphysematous patients it was normal. In a study 
of the effect of several drugs on the pressure in 
the pulmonary artery of unanesthetized dogs 
(/. Pharmacol., 1943, 77, 80), amyl nitrite is re- 
ported to have no effect. In such dogs, Stephens 
(/. Physiol, 1940, 99, 127) found that amyl 
nitrite caused contraction of the spleen. 

Cerebral. — In convulsive disorders, amyl ni- 
trite is of service only when it is necessary to 
cause immediate relaxation; thus in tetanus, be- 
cause of the duration of the convulsive tendency, 
the fugaciousness of its action renders it of rela- 
tively small service ; on the other hand, in strych- 
nine poisoning, by restraining the convulsions long 
enough for more durable motor depressants to 
act, it may prove a life-saving remedy. In ordi- 
nary epilepsy it is of little service, but in status 
epilepticus, in which the patient passes from one 
convulsion to another, the drug may be of great 
benefit. Again, in those occasional cases of epi- 
lepsy in which the seizure is preceded by an aura 
of sufficient length, inhalation of amyl nitrite as 
soon as the aura commences may abort the 
paroxysm. Brief cessation of the tremors in 
Parkinson's disease following inhalation of amyl 
nitrite has been reported by Garai {Arch. Neurol. 
Psychiat., 1951, 65, 452). 

Pulmonary. — In many cases of asthma it will 
cause an immediate, if only temporary, cessation 
of the paroxysm. Epinephrine and aminophylline 
are usually more effective. The claim of Hare that 
"amyl nitrite is of great value for the relief of 



hemoptysis has been confirmed by a number of 
observers (see Brit. M. L, July 15, 1911J. Its 
action in this condition is probably the result of 
dilatation of the splanchnic blood vessels. 

Colic. — Although the short-acting nitrites are 
of little value in most spasms of the gastrointes- 
tinal tract, they may be effective in lead colic 
{Arch. Int. Med., 1932, 49, 270) and may aid in 
the differentiation between spasm and organic 
lesions during x-ray examinations. These drugs are 
often beneficial in the relief of biliary colic {Surg., 
Gynec. Obst., 1936, 63, 451) both before and 
after cholecystectomy, including instances of 
biliary dyskinesia. Amyl nitrite is also indicated 
in the treatment of renal colic {Arch. urug. de 
med., 1944, 24, 105). Prytz (Ugeskr. f. laeger, 
1949, 111, 426) described its use, by inhalation, 
in obstetrics for the relief of constriction ring 
dystocia (BandFs contraction ring). It is also 
valuable in some cases of migraine (see Nicotinic 
Acid). In the management of cyanide poisoning, 
amyl nitrite plays an important role (see Diluted 
Hydrocyanic Acid). 

Amyl nitrite is generally administered by in- 
halation, usually in doses of from three to five 
drops, although much larger quantities have been 
given. The initial dose should be three drops on 
a handkerchief held close to the nose, the dose 
being gradually increased pro re nata. The hand- 
kerchief should be withdrawn as soon as the face 
flushes or severe palpitation is noted, as the effects 
increase for some time after inhalation is discon- 
tinued. The best method, however, of administer- 
ing the very volatile liquid is by the use of glass 
pearls — small flask-shaped vessels containing the 
nitrite; these are crushed in a handkerchief or 
towel when wanted for inhalation, the thin and 
fragile glass causing no inconvenience. The drug 
may also be given by mouth. 

Toxicology. — "When inhaled in doses of from 
five to ten drops, amyl nitrite produces in man 
violent flushing of the face, accompanied by a 
feeling as though the head would burst, and a very 
excessive action of the heart. Along with these 
symptoms, after a larger quantity, there is a sense 
of suffocation, and more or less marked muscular 
weakness. Since amyl nitrite increases intraocular 
tension, it must be used with caution in patients 
with glaucoma. In addition to the headache which 
it causes, it increases the pressure of the cerebro- 
spinal fluid and is contraindicated in patients 
suffering from head trauma, cerebral hemorrhage, 
etc. In some persons it produces a reaction com- 
parable to shock — nausea, vomiting, weakness, 
restlessness, pallor, sweating, syncope and incon- 
tinence — due to pooling of blood in the post- 
arteriolar vessels and failure of the return of 
venous blood to the heart {Arch. Int. Med., 1938, 
62, 97; /. Clin. Inv., 1938, 17, 41). Treatment 
consists of the head-low position, deep breathing 
and exercising the extremities to aid venous re- 
turn; the reaction is aggravated by epinephrine. S 

The usual dose is 0.3 ml. (approximately 5 
minims), by inhalation, as required. The maxi- 
mum safe dose is 0.3 ml. and the total dose in 24 
hours should rarely exceed 1.5 ml. 

Storage. — Preserve "in tight containers. Con- 
tainers for the administration of Amyl Nitrite by 



Part I 



Anethole 



91 



inhalation should be loosely wrapped in gauze or 
other suitable material." U.S.P. Horswell and 
Silverman (Ind. Eng. Chem., Anal. Ed., 1941, 13, 
555) reported that amyl nitrite, whether in vapor 
or liquid state, is stable in air and relatively stable 
when exposed to artificial light, but decomposes 
within two hours when exposed to direct sunlight. 

AMYLENE HYDRATE. U.S.P., B.P., LP. 

Tertiary Amyl Alcohol, [Amyleni Hydras] 

C2H B .C(CH 3 )2.0H 

The B.P. defines amylene hydrate as ethyl- 
dimethylcarbinol and states that it may be made 
by hydration of amylene (2-methylbutene-l). The 
I. P. defines the substance as 2-methyl-butanol-2. 

Dimethylethylcarbinol; Tertiary Pentanol. Amylenum 
Hydratum; Hydras Amylenicus. Fr. Hydrate d'amylene. 
Ger. Amylenhydrat; Tertiarer Amylalkohol. It. Idrato di 
amilene. Sp. H idrato de Amileno. 

Amylene hydrate, an alcohol, is prepared com- 
mercially by hydrating amylene, a hydrocarbon 
obtained by the chlorination of isopentane and 
hydrolysis of the resulting products. Hydration 
of the amylene is effected by treatment with a 
mixture of sulfuric acid and water at 0°; after 
neutralization of the acid the amylene hydrate is 
separated by distillation. 

Description. — "Amylene Hydrate occurs as 
a clear, colorless liquid, having a camphoraceous 
odor. Its solutions are neutral to litmus. One Gm. 
of Amylene Hydrate dissolves in about 8 ml. of 
water. It is miscible with alcohol, with chloro- 
form, with ether, and with glycerin. The specific 
gravity of Amylene Hydrate is not less than 0.803 
and not more than 0.807. Amylene Hydrate distils 
completely between 97° and 103°." U.S.P. The 
I. P. states that at temperatures below —13° 
amylene hydrate forms hygroscopic acicular 
crystals. 

Standards and Tests. — Identification. — (1) 
A mixture of amylene hydrate, sulfuric acid, 
potassium dichromate and water is heated for 2 
hours under a reflux condenser, forming acetic 
acid and acetone. These are removed by distilla- 
tion. Acetone, being the more volatile, distils over 
first and is identified in the first portion of dis- 
tillate by test (2). The remainder of the distillate 
is neutralized with sodium hydroxide T.S. and 
evaporated to dryness: the residue responds to 
tests for acetate. (2) A deep red liquid, developing 
a violent tint on dilution with water, is produced 
when sodium nitroprusside T.S. is added to a 
dilution of the reserved distillate, acidified slightly 
with acetic acid. (3) A violet red color results 
on adding 5 ml. of a 1 in 100 solution of vanillin 
in sulfuric acid to 10 ml. of a 1 in 10 solution of 
amylene hydrate. Water. — Anhydrous cupric sul- 
fate does not become blue when agitated with 
amylene hydrate. Non-volatile residue. — Not over 
25 mg. when 10 ml. of amylene hydrate is evapo- 
rated and finally dried at 105° for 1 hour. Heavy 
metals. — The limit is 5 parts per million. Readily 
oxidizable substances. — The pink color of a mix- 
ture of 10 ml. of 1 in 20 solution of amylene 
hydrate and 0.1 ml. of 0.1 N potassium per- 
manganate is not entirely discharged in 10 min- 
utes. Aldehyde. — No darkening occurs on heating 



a mixture of 10 ml. of 1 in 20 solution of amylene 
hydrate and 1 ml. of ammoniacal silver nitrate 
T.S. for 10 minutes at 60°. U.S.P. 

The B.P. test for limit of water is performed 
by adding fight petroleum to amylene hydrate; 
the resulting mixture should show no cloudiness. 

Uses. — In 1887 amylene hydrate, a central 
nervous system depressant, was proposed by Von 
Mering as a hypnotic. Advantages claimed were 
that it was quicker and more potent than paral- 
dehyde or sulfonal, and that it did not depress 
the heart like chloral hydrate. As a hypnotic it 
ranks between chloral hydrate and paraldehyde 
and it is relatively non-toxic. It was rarely used 
until it was employed as a vehicle for the basal 
anesthetic tribromoethanol. It is official because 
of this use (see Tribromoethanol Solution). 

Harnack and Meyer (Ztschr. klin. Med., 1894, 
24, 374) reported it produced quiet sleep in 
herbivorous animals but was an excitant to dogs 
and cats. It antagonized the convulsant effects of 
strychnine, picrotoxin and santonin, and in a 
general way its action was like that of alcohol. 
Barlow and Gledhill (/. Pharmacol, 1933, 49, 36) 
studied the effects of amylene hydrate on rats 
both alone and combined with tribromoethanol. 
They found the lethal dose, rectally or subcu- 
taneously, was about 1.4 Gm. per Kg. Although 
the rate of respiration was increased, the volume 
of air moved per minute was lessened by all doses. 
While it was possible to produce complete anes- 
thesia with amylene hydrate it required 65 per 
cent of the lethal dose and was accompanied by 
reduction of about 75 per cent in the volume of 
air breathed (Hofmann, Arch. exp. Path. Pharm., 
1936, 183, 127). 

In humans the hypnotic dose, dissolved in glyc- 
erin, is 1 to 4 Gm. Since the average dose of 
Tribromoethanol Solution contains over 2 Gm. 
of amylene hydrate, it may contribute to the 
hypnotic action of this solution. 

Amylene hydrate is an important commercial 
solvent; it is used especially in dry cleaning of 
cellulose acetate materials. 

Storage. — Preserve "in tight containers." 
U.S.P. 

Off. Prep. — Tribromoethanol Solution, U.S.P. , 
B.P. 

ANETHOLE. U.S.P. 

Anethol, [Anethole] 



CH,0 




^ / 



-CH=CHCH 3 



"Anethole is parapropenyl anisole. It is ob- 
tained from anise oil and other sources, or is pre- 
pared synthetically." U.S.P. 

Anise Camphor. l-Methoxy-4-propenylbenzene. 

Anethole occurs in several volatile oils. From 
80 to 90 per cent of anise oil is anethole; the 
latter may be separated by cooling the oil. Ane- 
thole may also be obtained from pine oil; indeed 
this oil was the only available source of anethole 
when supplies of anise oil were cut off during the 
Second World War. It may be synthesized from 
anisole and acetaldehyde. 



92 



Anethole 



Part I 



Description. — "Anethole is a colorless or 
faintly yellow liquid at or above 23°. It has a 
sweet taste, the aromatic odor of anise, and its 
alcohol solutions are neutral to litmus. It is af- 
fected by light. Anethole is readily miscible with 
ether and with chloroform. It dissolves in 2 vol- 
umes of alcohol. It is slightly soluble in water. 
The specific gravity of Anethole is not less than 
0.983 and not more than 0.988." U.S.P. 

Standards and Tests. — Congealing tempera- 
ture. — Not less than 20°. Distillation range. — 
Anethole distils completely between 231° and 
237°. Optical rotation. — Anethole is optically in- 
active or shows a rotation of not more than 0.15° 
in a 100-mm. tube. Refractive index. — Not less 
than 1.5570 and not more than 1.5610. Aldehydes 
and ketones. — No appreciable diminution in the 
volume of anethole occurs, nor does a crystalline 
deposit form, when 10 ml. of anethole is shaken 
with 50 ml. of a saturated aqueous solution of 
sodium bisulfite and /allowed to stand 6 hours. 
Phenols. — No purplish color is produced upon the 
addition of 3 drops of ferric chloride T.S. to 10 
ml. of the filtrate separated from 1 ml. of anethole 
shaken with 20 ml. of distilled water. U.S. P. 

Anethole is used like, and for the same pur- 
poses as, anise oil (which see). 

Dose, from 0.06 to 0.3 ml. (approximately 1 to 
5 minims). 

Storage. — Preserve "in tight, fight-resistant 
containers." U.S.P. 

Off. Prep. — Diphenhydramine Hydrochloride 
Elixir, U.S.P. ; Compound Cardamom Spirit, N.F. 

ANISE OIL. U.S.P., B.P. (LP.) 

[Oleum Anisi] 

"Anise Oil is the volatile oil distilled with steam 
from the dried, ripe fruit of Pimpinella Anisum 
Linne (Fam. Umbelliferce) or from the dried, ripe 
fruit of Illicium verum Hooker filius (Fam. Mag- 
noliacece). Note. — If solid material has separated 
from Anise Oil, carefully warm the mixture 
until it is completely liquefied, and mix it thor- 
oughly before using." U.S.P. The B.P. and LP. 
recognize oil distilled from the same plant sources. 

I. P. Oil of Anise. Oil of Aniseed. Oleum Anisi 
^thereum; Essentia anisi. Fr. Essence d'anis. Ger. Ani- 
sol. It. Essenze di anice. Sp. Esencia de anis. 

Anise oil, which is imported into this country 
chiefly from India and French Indo-China, is ob- 
tained mostly from Illicium verum, or Star Anise, 
which is described in Part II under the title 
Illicium. For a description of Pimpinella Anisum 
see under Anise, in Part II. 

Description. — "Anise oil is a colorless or pale 
yellow, strongly refractive liquid, having the char- 
acteristic odor and taste of anise. One volume of 
Anise Oil dissolves in 3 volumes of 90 per cent 
alcohol. The specific gravity of Anise Oil is not 
less than 0.978 and not more than 0.988." U.S.P. 

Standards and Tests. — Congealing tempera- 
ture. — Not below 15°. Optical rotation. — The 
optical rotation in a 100-mm. tube, at 25°, is be- 
tween + 1° and —2°. Refractive index. — Not less 
than 1.5530 and not more than 1.5600, at 20°. 
Heavy metals. — The oil meets the official require- 
ments. Phenols. — A 1 in 3 solution of recently 



distilled anise oil in 90 per cent alcohol is neutral 
to moistened litmus paper, and the solution de- 
velops no blue or brown color on adding 1 drop 
of ferric chloride T.S. to 5 ml. of it. U.S.P. 

Constituents. — Anise oil contains 80 to 90 
per cent of anethole (which see), together with 
small amounts of its isomer methyl-chavicol, of 
anisaldehyde, and of terpenes. 

Adulterants. — Because of its high price anise 
oil is often adulterated. Spermaceti, wax and 
camphor are adulterants that have been used in 
times past; fennel stearoptene has been found 
also. The so-called Japanese star anise oil (from 
Illicium anisatum), with which the official oil may 
be confused, is derived from leaves, rather than 
fruit, and contains eugenol and safrol, and much 
less anethole than the oil from the fruit (see 
Illicium, Part II). 

Uses. — Anise oil is one of the most popular of 
flavoring agents. Therapeutically it is useful to 
stimulate peristalsis in colic and as an expectorant. 
Boyd and Pearson (Am. J. Med. Sc, 1946, 211, 
602) found it to be more effective than the oils of 
turpentine, pine, lemon or eucalyptus. They be- 
lieve that the expectorant volatile oils act directly 
on the secretory cells of the respiratory tract. 
Anise oil has also been recommended as a means 
of destroying body lice. Parutz (Schim. Rep., 
1920) used a 1 per cent ointment for scabies. The 
N.F. IX recognized Anise Spirit, a 10 per cent 
v/v solution of the oil in alcohol, also Anise 
Water, a saturated solution of the oil in distilled 
water. 

Dose, of the oil, 0.2 to 0.3 ml. (approximately 
3 to 5 minims). 

Storage. — Preserve "in well-filled, tight con- 
tainers and avoid exposure to excessive .heat." 
U.S.P. 

Off. Prep. — Glycyrrhiza Syrup; Compound 
Orange Spirit, U.S. P.; Aromatic Cascara Sagrada 
Fluidextract; Camphorated Opium Tincture, 
U.S. P., B.P.; Compound Sarsparilla Syrup, N.F. 

ANTAZOLINE HYDROCHLORIDE. 

U.S.P.. LP. 

Antazolinium Chloride, 2-(N-Benzylanilinomethyl)-2- 
imidazoline Hydrochloride 



\ \-CH 2 -N-CH 2 -r^ ^ 

^ ' ^-^ HM 1 



HN- 



cr 



"Antazoline Hydrochloride, dried at 105° for 3 
hours, contains not less than 98 per cent of 
C17N19N3.HCI." U.S.P. The LP. rubric is the 
same, referred to the substance as it occurs. 

I. P. Antazolini Hydrochloridum. 2-(N-Phenyl-N-benzyl- 
aminomethyl)imidazoline Hydrochloride. Antistine Hydro- 
chloride (Ciba). Phenazoline Hydrochloride. 

This antihistaminic substance is characterized 
by the fact that the side chain (see article on 
Antihistaminic Drugs, in Part II), which in many 
such compounds is a dialkylaminoethyl group, has 
been replaced by an imidazoline radical, thus 



Part I 



Antazoline Hydrochloride 93 



making antazoline similar to the sympathomimetic 
drugs Privine [2-(l-naphthylmethyl)-2-imidazo- 
line] and Otrivine [(2-anilinomethyl)-2-imidazo- 
line] . Antazoline may be synthesized by the inter- 
action of anilinomethylimidazoline and benzyl 
chloride, the first reactant being prepared from 
anilinoacetimidoester and ethylenediamine (see 
Idson, Chem. Rev., 1950, 47, 340). 

Description. — "Antazoline Hydrochloride oc- 
curs as a white, odorless, crystalline powder. Its 
solutions are neutral to litmus. One Gm. of 
Antazoline Hydrochloride dissolves in about 40 
ml. of water, and in about 25 ml. of alcohol. It 
is practically insoluble in chloroform, in ether, 
and in benzene. Antazoline Hydrochloride melts, 
with decomposition, between 232° and 238°." 
U.S.P. 

Standards and Tests. — Identification. — (1) 
A deep red color is produced when 25 mg. of 
antazoline hydrochloride is dissolved in 5 ml. of 
nitric acid, the color persisting when the solution 
is diluted with 20 ml. of water. (2) A 1 in 100,000 
solution exhibits an ultraviolet absorbancy maxi- 
mum at 242 mn ± 1 mjx, and a minimum at 222 
m\t ± 1 mn; the specific absorbancy, E(l%, 
1 cm.), at 242 m\i is between 495 and 515. (3) 
Antazoline hydrochloride responds to tests for 
chloride. Loss on drying. — Not over 0.5 per cent, 
when dried at 105° for 3 hours. Residue on igni- 
tion. — Not over 0.2 per cent. U.S.P. 

Assay. — About 600 mg. of antazoline hydro- 
chloride, dried at 105° for 3 hours, is dissolved in 
80 ml. of glacial acetic acid and, after adding 
10 ml. of mercuric acetate T.S., is titrated with 
0.1 N perchloric acid, the end-point being deter- 
mined potentiometrically. Each ml. of 0.1 N 
perchloric acid represents 30.18 mg. of C17H19- 
N3.HCI. U.S.P. This non-aqueous titration is 
based upon the principle that each molecule of 
antazoline base represented in the sample releases 
one acetate ion when the salt is dissolved in acetic 
acid. Each acetate ion, being basic, in turn com- 
bines with a hydrogen ion released by perchloric 
acid, forming a molecule of acetic acid. Since the 
solvent medium is acetic acid, this reaction is one 
of neutralization, comparable to the combination 
of hydrogen and hydroxyl ions to form water 
when the latter is the solvent medium. The pur- 
pose of adding mercuric acetate is to prevent in- 
terference by the hydrochloride component of the 
salt, which reacts with the mercuric acetate to 
form acetic acid and non-ionized mercuric chlo- 
ride (for additional information see Kleckner and 
Osol, /. A. Ph. A., 1952, 41, 573). The LP. assays 
the substance gravimetrically as the picrate. 

Uses. — This drug has received extensive phar- 
macological and clinical study. Its antihistaminic 
activity in animals is 10 to 20 per cent of that of 
tripelennamine hydrochloride, but its toxicity is 
likewise low (Meier and Bucher, Schweiz. med. 
Wchnschr., 1946, 76, 294; Craver et al., Ann. 
Allergy, 1951, 9, 34). Used prophylactically, it 
protects the guinea pig from anaphylactic shock 
and in human skin it prevents wheal formation 
following injection of histamine or of the specific 
allergen in the allergic patient (Serafini, /. Allergy, 
1948, 19, 256; Schwartz and Wolf, ibid., 1949, 
20, 32). Dutta (Brit. J. Pharmacol. Chemother., 



1949, 4, 281) reported it to have 2.3 times the 
local anesthetic effect of procaine hydrochloride; 
he also observed it to have antiacetylcholine action 
and a more intense effect than that of quinidine 
in decreasing the response of muscle to electrical 
stimulation. Its use does not prevent a positive 
tuberculin patch test (Kendig et al., J. Pediat., 
1949, 35, 750) and it does not increase or de- 
crease the antibody titer following diphtheria- 
tetanus toxoid (Regamey and Wantz, Schweiz. Zt. 
Path. Bakt., 1947, 10, 426). 

Many clinical reports have appeared on its use 
in allergic disorders. A number of these have been 
summarized by Loveless and Dworin (Bull. N. Y. 
Acad. Med., 1949, 25, 473), with the general con- 
clusion that while a lower percentage of thera- 
peutic effectiveness was found than with most 
other antihistamines, the incidence of untoward 
effects was likewise among the lowest. Friedlaender 
and Friedlaender (Ann. Allergy, 1948, 6, 23) con- 
cluded that 100 mg. of antazoline hydrochloride 
is clinically equivalent to 50 mg. of tripelennamine 
hydrochloride. Antazoline was found to be the 
least effective of 13 antihistaminics tested by 
Sternberg et al. (J.A.M.A., 1950, 142, 969) for 
ability to raise the histamine whealing threshold 
in man. 

Antazoline absorbs the erythema-producing 
wave lengths of the ultraviolet region (Fried- 
laender et al, J. Invest. Derm., 1948, 11, 397). 
Studies of the living mesoappendix by Haley and 
Harris (/. Pharmacol, 1949, 95, 293) showed 
that it causes contraction of the precapillary 
sphincter. 

Since it is less irritating than some other anti- 
histaminics antazoline hydrochloride is used in an 
0.5 per cent buffered (pH 6.1) isotonic solution 
in the conjunctival sac (see reference to use of 
antazoline phosphate below) and the nose (Fried- 
laender and Friedlaender, loc. cit.). Hurwitz (Am. 
J. Ophth., 1948, 31, 1409) reported relief of 
allergic eye conditions with one drop of this solu- 
tion applied every 3 or 4 hours; momentary 
smarting was observed. Taub et al. (Am. Pract., 
1949, 3, 664), however, do not advise use of this 
solution because of the short period of sympto- 
matic relief and the danger of sensitizing the 
tissue to the drug. A solution containing 0.025 per 
cent naphazoline hydrochloride and 0.5 per cent 
antazoline hydrochloride is intended for nasal use 
by application in the form of drops, spray, or by 
tampon; the antihistamine component also pos- 
sesses vasoconstrictive action. The solution is in- 
dicated in allergic and vasomotor rhinitis, sinusitis 
and, perhaps, in the common cold. A concentra- 
tion in excess of 1:1000 inhibits ciliary activity 
(Craver et al, loc. cit.). See also the general dis- 
cussion of Antihistaminic Drugs in Part II. 

The untoward effects are similar to those of 
other antihistamines but the incidence is lower, 
with the possible exception of thonzylamine. 
Nausea and drowsiness are most frequent. Intra- 
venously the drug must be given very slowly to 
minimize flushing and vertigo; the dose by this 
route should not exceed 50 to 100 mg. 

Dose. — The usual dose is 100 mg. (approxi- 
mately \Yz grains) up to 4 times daily by mouth, 
with a range of 50 to 100 mg. The maximum safe 



94 Antazoline Hydrochloride 



Part I 



dose is 100 mg. and the total dose in 24 hours 
should generally not exceed 400 mg. 

A 0.5 per cent solution in isotonic sodium 
chloride solution is used in the nose. For oph- 
thalmic use, a 0.5 per cent isotonic solution of 
Antazoline Phosphate (N.N.R.), is preferable to 
that prepared from the hydrochloride because it 
produces less smarting and stinging. 

Storage. — Preserve "in tight, light-resistant 
containers." U.S.P. 

ANTAZOLINE HYDROCHLORIDE 
TABLETS. U.S.P. 

"Antazoline Hydrochloride Tablets contain not 
less than 93 per cent and not more than 107 per 
cent of the labeled amount of C17H19N3.HCI." 
U.S.P. 

Assay. — The antazoline hydrochloride in a 
representative portion of powdered tablets is ex- 
tracted with alcohol and the content of the active 
ingredient calculated from observation of the 
absorbancy at the wavelength of maximum ab- 
sorption, in this case 242 mn. While the position 
of the absorbancy maximum in the case of anta- 
zoline hydrochloride is the same in both alcohol 
and water solution, which is not the case with all 
antihistaminic drugs similarly assayed, there is 
somewhat more intense absorption in alcohol solu- 
tion, which accounts for the difference in values 
of specific absorbancy given for the water solution 
employed in identification test (2) under anta- 
zoline hydrochloride and for the alcohol solution 
employed in the assay of the tablets. U.S.P. 

Usual Size. — 100 mg. (approximately 1J^ 
grains). 

ANTHRALIN. N.F. (B.P.) 

[Anthralinum] 
H OH OH 




"Anthralin. dried over sulfuric acid for 4 hours, 
contains not less than 95 per cent of C14H10O3." 
N.F. Under the title Dithranol the B.P. defines 
this substance as 1,8-dihydroxyanthranol; no assay 
rubric is stipulated. 

B.P. Dithranol. Dioxyanthranol; 1,8,9-Anthratriol. 
Cignolin (Winthrop). 

This chrysarobin substitute may be synthesized 
by reducing l,S-dihydroxyanthraquinone, the lat- 
ter obtained by heating with lime the 1,8-anthra- 
quinonedisulfonic acid prepared by sulfonation of 
anthraquinone in the presence of mercury. 

The 1,8-dihydroxyanthraquinone, which is the 
parent substance of anthralin, is closely related 
to chrysophanol, structurally l,8-dihydroxy-3- 
methylanthraquinone, which is the parent com- 
pound of the constituents of chrysarobin (q.v.) 
and is itself an important constituent of cascara, 
rhubarb and senna. As might be expected, 1.8-di- 
hydroxyanthraquinone is laxative, being official 
as Danthron. 



Description. — "Anthralin occurs as an odor- 
less, tasteless, crystalline, yellowish brown pow- 
der. When suspended in water and filtered, the 
filtrate is neutral to litmus paper. Anthralin is 
soluble in chloroform, in acetone, and in benzene. 
It is soluble in solutions of alkali hydroxides. It 
is slightly soluble in alcohol, in ether, and in 
glacial acetic acid. It is insoluble in water. An- 
thralin melts between 175° and 181V' N.F. The 
B.P. indicates anthralin to be soluble in fixed oils. 
Standards and Tests. — Identification. — (1) 
A yellowish to orange solution, having a green 
fluorescence, results when anthralin is dissolved 
in sodium hydroxide T.S.; on exposure to air the 
solution turns to a strong orange-red color. (2) 
A greenish brown color is produced when anthra- 
lin is dissolved in alcohol and ferric chloride T.S. 
is added. Chloride. — Addition of silver nitrate 
T.S. to a saturated solution of anthralin produces 
no opalescence. Sulfate. — Addition of barium 
chloride T.S. to a saturated solution of anthralin 
produces no turbidity. Loss on drying. — Not over 
0.5 per cent, when dried over sulfuric acid for 4 
hours. Residue on ignition. — The residue from 500 
mg. is negligible. N.F. The B.P. specifies, as a test 
to exclude dihydroxyanthracene, that 100 mg. of 
anthralin should dissolve completely in 5 ml. of 
hot benzene, forming a clear yellow or orange 
solution. As a test to exclude dihydroxy anthra- 
quinone 1 mg. is required to produce a clear 
orange solution in a few drops of sulfuric acid, no 
trace of violet color being evident. The loss on 
drying to constant weight at 100° should not be 
more than 1 per cent and the ash should not ex- 
ceed 0.1 per cent. 

Assay. — Using a chloroform solution contain- 
ing 0.01 mg. of anthralin per ml. optical .density 
readings are taken at 354 mn and at 432 mn in a 
suitable spectrophotometer and the corresponding 
values of E(l%, 1 cm.) are calculated. The con- 
tent of anthralin is calculated by means of an 
equation utilizing a difference function of the E 
values. iVJ 7 . No assay is specified by the B.P. 

Uses. — Anthralin has the action and uses of 
chrysarobin (q.v.) over which it has several ad- 
vantages, as follows: It is a definite compound, 
rather than an indefinite mixture; it is effective 
at lower concentrations; it is less irritant to the 
skin, conjunctiva and kidneys; it causes less 
coloration of clothing (Beerman et al., J. A.M. A., 
1935, 104, 26, 48). 

Anthralin is used in psoriasis, dermatophytoses, 
chronic eczemas, alopecia areata and other dis- 
eases of the skin in which a stimulant application 
is indicated. Goodman (Arch. Derm. Syph., 1939, 
40, 76) warned against its prolonged use because 
exhaustion of the epidermal tissues may result. 
The drug should be discontinued if pustular 
folliculitis or renal irritation develops. 

Anthralin is usually employed in concentrations 
of 0.1 to 1 per cent, in the form of an ointment 
or cream, in a benzene solution, or in a collodion 
vehicle; the lowest concentration should be em- 
ployed first, then increased if found necessary 
and well-tolerated. 

Storage. — Preserve "in tight containers, pro- 
tected from light." N.F. 



Part I 



Antimony Potassium Tartrate 95 



ANTHRALIN OINTMENT. N.F. (B.P.) 

[Unguentum Anthralinum] 

"Anthralin Ointment labeled to contain more 
than 0.1 per cent of anthralin (C14H10O3) con- 
tains not less than 90 per cent and not more than 
115 per cent of the labeled quantity of C14H10O3 
and contains not more than 115 per cent of 
C14H10O3 and 1,8-dihydroxyanthraquinone (C14- 
H8O4) combined. Not more than 10 per cent of 
the labeled quantity of anthralin is C14H8O4. 

"Anthralin Ointment labeled to contain 0.1 per 
cent or less of C14H10O3 contains not less than 
90 per cent and not more than 130 per cent of 
the labeled quantity of C14H10O3 and not more 
than 130 per cent of C14H10O3 and C14H8O4 com- 
bined. Not more than 20 per cent of the labeled 
quantity of anthralin is C14H8O4." N.F. 

B.P. Ointment of Dithranol; Unguentum Dithranolis. 

Anthralin ointment may be prepared by thor- 
oughly mixing 10 Gm. of finely powdered anthra- 
lin with a portion of white petrolatum and then 
incorporating sufficient white petrolatum to make 
1000 Gm. Due to slow oxidation of anthralin to 
1,8-dihydroxyanthraquinone upon standing, oint- 
ments intended not to be used for some time 
should be prepared with about 5 per cent excess 
of anthralin for ointments containing more than 
0.1 per cent, and a 20 per cent excess of anthralin 
for ointments containing 0.1 per cent or less. N.F. 

The B.P. recognizes Ointment of Dithranol, 
containing 0.1 per cent of dithranol in a base of 
yellow soft paraffin (yellow petrolatum), and a 
Strong Ointment of Dithranol, containing 1 per 
cent of dithranol in the same base. 

For uses of anthralin ointment, see the preced- 
ing monograph. 

Storage. — Preserve "in well-closed, light- 
resistant containers." N.F. 



ANTIMONY 
Sb (121.76) 

Stibium. Fr. Antimoine. Ger. Antimon. It. Antimonio. 
Sp. Antimonio. 

Antimony, earlier called stibium, may have been 
known as long ago as 4000 B.C. In ancient times 
it was employed as a medicine and as a cosmetic. 
Late in the 15th century Basil Valentine described 
its preparation and his observations of properties 
of the element and some of its compounds. 

The free element is found in nature in rela- 
tively small amounts. Its chief ore, stibnite 
(Sb2S3), occurs rather abundantly, especially in 
China, Mexico, Bolivia, Algeria, Portugal and 
France; comparatively few deposits have been 
found in the United States. The metal is obtained 
either by heating stibnite with scrap iron, or by 
roasting the ore to convert it to oxides of anti- 
mony which are subsequently reduced to metal 
by heating with carbon. 

Properties. — Antimony is a brittle, brilliant 
metal, ordinarily of a lamellated texture, of a 
silver-white color when pure, but bluish white as 
it occurs in commerce. Its density is about 6.7, 
and it melts at 630°. When heated in oxygen it 



burns with a bright bluish flame, forming the 
trioxide. Several allotropic forms may be pre- 
pared by special treatment. It forms three com- 
binations with oxygen, antimony trioxide (anti- 
monious oxide), SD2O3, antimony tetr oxide, Sb204 
(by some considered to be an antimonate of the 
radical antimonyl, SbO.SbOs), and antimony pent- 
oxide (antimonic oxide), Sb20s. 

By virtue of the fact that antimony has the 
property of imparting hardness to metals, par- 
ticularly lead, it is used in the manufacture of 
lead alloy for storage battery plates, in Babbitt 
metal and other antifriction alloys, in pewter and 
Britannia metal, in type metal, and in other alloys. 
It has the important property of expanding on 
cooling which, in type metal, makes it possible 
to obtain an accurate cast of a letter. Antimony 
has been used as an alloy with lead for shrapnel 
and the bullet cores of small arms ammunition. 
One of the important newer uses of compounds 
of antimony is that of antimony trioxide in flame- 
proofing compounds for application to military 
and household textiles. Large amounts of anti- 
mony trisulfide and antimony pentasulfide are 
used in the rubber industry for producing vul- 
canized rubber of red color. 

Inorganic antimony compounds are not em- 
ployed in therapeutics because of their toxicity, 
but a number of organic compounds are safe 
enough to use. The activity of antimonials is 
proportional not merely to their solubility in the 
gastric juices but, according to the researches of 
Brunner (Arch. exp. Path. Pharm., 1912, 68, 
186), especially depends upon whether the metal 
is in the trivalent or pentavalent condition, the 
latter being comparatively innocuous (see the 
study by Goodwin, /. Pharmacol., 1944, 81, 224). 
In recent years organic preparations of antimony 
have received considerable attention as thera- 
peutic agents in various protozoal diseases (see 
Antimony Potassium Tartrate, Antimony Sodium 
Thiogly collate, Stibophen, and the article on Anti- 
monials, Organic, in Part II). For a comprehen- 
sive report on the toxicology of antimony see 
Fairhall and Hyslop (Supplement No. 195 to the 
Public Health Reports, 1947). 

ANTIMONY POTASSIUM TARTRATE 
U.S.P., B.P. (LP.) 

Antimonyl Pot.'.ssium Tartrate, Tartar Emetic, 
[Antimonii Potassi Tartras] 

"Antimony Potassium Tartrate contains not less 
than 99 per cent of C4H4K0 7 Sb.^H 2 0." U.S.P. 
The B.P. and LP. rubrics are the same. 

I. P. Potassium Antimonyltartrate ; Stibii et Kalii 
Tartras. Tartrated Antimony. Antimonium Tartaratum; 
Tartarus Stibiatus; Kalium Stibio Tartaricum; Stibii et 
Potassii Tartras; Tartarus Emeticus. Fr. Antimoniotar- 
trate acide de potassium; Tartre stibie; Tartrate d'anti- 
moine et de potasse. Ger. Brechweinstein ; Weinsaures 
Antimonylkalium. It. Tartrato di antimonio e di potas- 
sio; Tartaro stibiato. Sp. Tartrato de antimonio y de 
potasio; Tartrato Potdsico Antimonico; Tartaro estibiado. 

Antimony potassium tartrate may be prepared 
by the interaction of antimony trioxide and potas- 
sium bitartrate. 

The structure of this salt is a subject of contro- 
versy. Reihlen and Hezel (Ann. Chem., 1931, 487, 



96 Antimony Potassium Tartrate 



Part I 



213) proposed a cyclic structure in which the 
water is attached by coordination to the antimony, 
as follows: 



0:C 




OH 2 



Evidence for this cyclic structure has been ob- 
tained also by Pfeiffer and Schmitz (Pharmazie, 
1949, 4, 451). 

Description. — "Antimony Potassium Tartrate 
occurs as colorless, odorless, transparent crystals, 
or as a white powder. The crystals effloresce upon 
exposure to air. Its solutions are acid to litmus. 
One Gm. of Antimony Potassium Tartrate dis- 
solves in 12 ml. of water and in about 15 ml. of 
glycerin. One Gm. dissolves in about 3 ml. of boil- 
ing water. It is insoluble in alcohol. U.S.P. 

Standards and Tests. — Identification. — (1) 
Antimony potassium tartrate chars, emits an odor 
like that of burning sugar, and leaves a blackened 
residue when heated to redness; the residue is 
alkaline and confers a violet tint to a non-lumi- 
nous flame. (2) An orange red precipitate forms 
on adding hydrogen sulfide T.S. to a 1 in 10 solu- 
tion of antimony potassium tartrate, acidified with 
hydrochloric acid; the precipitate dissolves in am- 
monium sulfide T.S. and in sodium hydroxide T.S. 
Arsenic. — The limit is 200 parts per million. 
U.S.P. The B.P. limits for arsenic and lead are 
8 parts per million and 5 parts per million, re- 
spectively; the corresponding LP. limits are 10 
parts per million and 5 parts per million. 

Assay. — About 500 mg. of antimony potassium 
tartrate is dissolved in water, a saturated solution 
of sodium bicarbonate is added, and the trivalent 
antimony is oxidized to the pentavalent state by 
titration with 0.1 N iodine, employing starch T.S. 
indicator. Each ml. of 0.1 N iodine represents 
16.70 mg. of C4H4K07Sb.^H 2 0. U.S.P. The 
B.P. and LP. assays are practically identical with 
that of the U.S.P. 

Incompatibilities. — Mineral acids added to 
aqueous solutions of tartar emetic precipitate the 
respective basic salts of antimony, with possibly 
some potassium bitartrate. Alkali hydroxides and 
carbonates, in sufficient amounts, precipitate anti- 
mony trioxide, soluble in excess of fixed alkali. 
The precipitation may be prevented by an excess 
of citrates, tartrates, glycerin, or sugar. Most 
metallic salts, including those of lead and silver, 
form insoluble tartrates when added to aqueous 
solutions of tartar emetic. Tannic and gallic acids, 
or infusions of tannin-containing drugs, yield 
precipitates with tartar emetic. Solutions of al- 
bumin and of soap behave similarly. Lime water 
forms insoluble calcium and antimony tartrates; 
mercuric chloride is reduced to calomel. 

Uses. — Tartar emetic is a slow-acting local 
irritant, capable of causing not only redness but 
also vesicles and pustules at the orifices of the 
glands of the skin; this action appears to be 
associated with the formation of antimony tri- 
oxide. It has been used as a counterirritant in 
the form of an ointment or plaster. 



When taken internally, tartar emetic provokes 
salivation and nausea; in sufficient dose active 
vomiting occurs. The emetic effect is the result 
chiefly of the local irritant action of antimony 
upon the gastric mucosa. This is true even when 
the drug is injected hypodermicWly, because it is 
excreted through the walls of the stomach in 
sufficient quantity to act as an irritant. On the 
other hand, the drug will produce vomiting move- 
ments in the dog even after complete removal of 
the stomach (Hatcher and Weiss, /. Exp. Med., 
1923, 37, 97). Tartar emetic is poorly absorbed 
from the gastrointestinal tract. 

When absorbed into the circulation, as by in- 
travenous injection, the antimony solution causes 
a marked lowering of blood pressure, decreased 
cardiac output, dilatation of the splanchnic ves- 
sels, increased pressure in the pulmonary vessels 
and, in large doses, respiratory depression. Changes 
in the electrocardiogram occur in patients treated 
with antimony compounds, more frequently when 
tartar emetic is used than when other organic 
antimonials are employed; these changes have 
not been permanent and seemed to have no seri- 
ous clinical import (see Mainzer and Krause, 
Trans. Roy. Soc. Trop. Med. Hyg., 1940, 33, 
405; Tarr, Bull. U. S. Army M. Dept., 1946, 5, 
336; Schroeder et ah, Am. J. Med. Sc, 1946, 
212, 697). 

Tartar emetic is excreted rapidly (see also 
under Stibophen) , elimination being almost com- 
plete in 72 hours. It is found in the urine; large 
doses cause signs of renal irritation. Kramer 
{Bull. Johns Hopkins Hosp., 1950, 86, 179) re- 
ported a higher concentration of antimony in the 
thyroid of the rabbit than in any other tissue 
except the fiver but no histological or functional 
abnormality was observed. 

While it is a powerful emetic, antimony has 
been almost completely abandoned for such use 
in favor of less dangerous and equally efficient 
emetic drugs. It is, however, still occasionally em- 
ployed as a nauseant expectorant in the treatment 
of acute bronchitis and is an ingredient of some 
cough syrups. Its use should be avoided in very 
young or very- old persons, also in persons with 
feeble circulation. 

Tartar emetic and other antimony compounds 
(see Stibophen and Antimonials, Organic) have 
been used widely in treating various tropical in- 
fections. Chemotherapy with heavy metal com- 
pounds usually depends on a differential toxicity 
whereby the parasites are destroyed or made sus- 
ceptible to cellular or humoral defense mechan- 
isms of the body by a dose of the metallic com- 
pound which is insufficient to cause serious damage 
to the host; while this general statement is 
applicable to antimony compounds, the exact 
mechanism of their action has not been elucidated 
(see Most and Lavietes, Medicine, 1947, 26, 221). 
In an in vitro study of several antimony com- 
pounds Mansour {Brit. J. Pharmacol. Chemother., 
1951, 6, 588) observed paralysis of the liver fluke. 
Fasciola hepatica, only if 50 per cent of blood 
serum was added to a 1:1000 solution of tartar 
emetic; stibophen was not active, either alone or 
in the presence of serum. 



Part I 



Antimony Potassium Tartrate 97 



In schistosomiasis japonica, the War Depart- 
ment, U.S.A. (TB Med 167, see War Med., 1945, 
7, 397) recommended use of Fuadin (see Stibo- 
phen) or antimony potassium tartrate. The latter 
is administered intravenously, slowly, about 2 or 
3 hours after a light meal. The needle must be 
wiped off before insertion and there must be no 
extravasation of the solution. The patient should 
remain recumbent for at least an hour after the 
injection. For the first dose 8 ml. of 0.5 per cent 
solution is given; on alternate days the dose is 
increased by 4 ml. each time until a maximum 
dose of 28 ml. is reached, which is repeated 15 
times. Coughing immediately upon injection is a 
common though unimportant untoward effect; 
this may be minimized by injecting slowly, at a 
rate not exceeding 8 ml. per minute. Other toxic 
manifestations include nausea, vomiting, stiffness 
of the joints and muscles, sensation of constric- 
tion in the chest, pain in the epigastrium, brady- 
cardia, dizziness and collapse; if any of these 
symptoms occurs during the injection, it should 
be stopped. Subsequent doses should be decreased 
or omitted entirely, depending on the severity of 
the reaction. If viable eggs persist four weeks 
after the completion of the course of injections, 
the course should be repeated, or another drug 
employed, if the patient can tolerate it. When 
instituted early, this treatment prevents develop- 
ment of severe sequelae. If cirrhosis of the liver 
has developed, the treatment cannot correct it. 
Injections should not be given in the presence of 
severe disease of the heart, liver or kidney. Gen- 
erally, other heavy metals or emetine should not 
be given at the same time. Beneficial effects have 
been obtained with similar treatment regimens 
employed against Schistosoma mansoni and 
S. haematobium (see the extensive review Ad- 
vances in the Therapeutics of Antimony, Schmidt 
and Peter, Leipzig, 1938). Successful treatment 
of a case of cerebral schistosomiasis manifesting 
Jacksonian convulsive seizures has also been re- 
ported (Salis and Smith, Ann. Int. Med., 1951, 
34, 238). 

For granuloma inguinale (characterized by the 
presence of Donovan bodies in the lesion and not 
to be confused with the venereal, "virus" disease 
lymphogranuloma inguinale), the "broad-spec- 
trum" antibiotics, such as aureomycin (q.v.), have 
proved to be more effective, safer and much easier 
to use than antimony compounds. Tartar emetic 
has, however, been rather extensively employed, 
one of the treatment programs, recommended 
when a course of stibophen had failed after six 
weeks (see TB Med 157, Bull. U. S. Army M. 
Dept., 1945, 4, 326), consisting of the initial in- 
jection of 3 ml. of 1 per cent solution, given 
slowly intravenously, repeated on alternate days 
with an increase in the dose of 3 ml. each time 
until 12 ml. is reached, which is given 15 times. 

Tartar emetic was the first successful form of 
therapy for visceral leishmaniasis (kala-azar), 
but the treatment was prolonged, uncomfortable 
and difficult, with toxic effects often preventing 
satisfactory clinical results; it is therefore not 
recommended for such use, Neostibosan (see 
Part II) being advised instead. Tartar emetic 



has been used effectively in the treatment of 
oriental sore. Mucocutaneous leishmaniasis in 
South America has been treated with an initial 
dose of 4 ml. of a 1 per cent solution of tartar 
emetic, this being increased by 1 ml. at each in- 
jection to a maximum dose of 10 ml., at which 
level injections were given twice weekly for about 
six weeks (Snow et al., Arch. Dermat. Syph., 
1948, 57, 90) ; combined therapy with arsenic 
and antimony (stibophen) is, however, preferred. 

Tartar emetic has been employed in trypano- 
somiasis but arsenicals (see Tryparsamide) are 
less toxic, and diamidines (see in Part II) seem 
to be more effective. It has failed in the treatment 
of clonorchiasis ; it is of possible value in filariasis 
but is not recommended (War Med., 1945, 7, 
377). Cochrane (Med. Press, May 9, 1945) ad- 
vised on alternate days 3 doses of 20 mg. fol- 
lowed by 3 doses of 40 mg. for the true lepra- 
reaction in leprosy. It has been employed for 
trachoma with corneal complications (Brit. M. J., 
1939, 1, 516) and for trypanosomiasis in cattle 
(Cawston, /. Trop. Med. Hyg., 1935, 38, 305). 
It was also recommended by Rogers (Brit. M. J., 
Jan. 6, 1917) for the destruction of the crescents 
in the treatment of tertian malarial fever. Grove 
(J.A.M.A., 1925, 85, 349) reported a case of 
trichinosis in which the larvae were demonstrated 
in the blood stream, and in which, following the 
intravenous injection of a solution of tartar 
emetic, the symptoms promptly subsided and the 
parasites disappeared from the blood. Tomlinson 
and Bancroft (J.A.M.A., 1934, 102, 36) reported 
two cases of that rare and often fatal mycodermal 
infection known as granuloma coccidioides, which 
were apparently cured by its intravenous use. 

Tartar emetic has recently been recommended 
as a spray in the control of thrips on lemons, 
gladioli, and onions. lYl 

Poisoning. — Symptoms of acute poisoning by 
the drug are an austere metallic taste, excessive 
nausea, copious vomiting, frequent hiccough, 
burning pain in the stomach, colic, frequent stools 
and tenesmus, fainting, rapid and feeble pulse, 
coldness of the skin, and even of the internal 
organs, difficult and irregular respiration, cutane- 
ous anesthesia, convulsive movements, painful 
cramps in the legs, anuria, prostration, and death. 
In rare cases vomiting and purging do not take 
place, and when they are absent, the other symp- 
toms are aggravated. Sometimes a pustular erup- 
tion is produced, like that caused by the external 
application of the antimonial. Although because 
of the promptness of its emetic action recovery 
may occur after very large amounts, one case is 
on record in which 130 mg. proved fatal. 

The symptoms of antimony poisoning fre- 
quently so closely resemble those of arsenic that 
a diagnosis may be well-nigh impossible except 
through chemical examinations. The post-mortem 
lesions also resemble those of arsenic poisoning; 
commonly ulcerations are found in the esophagus 
and stomach — although sometimes lacking — but 
rarely in the intestines. In the less acute cases 
there also develop fatty degenerations of the 
liver, kidneys or heart, and sometimes also de- 
generative changes in the nervous system. 



98 Antimony Potassium Tartrate 



Part I 



In the treatment of antimony poisoning, even 
though the patient has vomited, it is usually 
advisable to wash out the stomach, using a solu- 
tion of tannic acid. Tannic acid should be ad- 
ministered repeatedly as the poison is eliminated 
from the blood through the walls of the stomach. 
The use of milk or albumin water as demulcents, 
opiates to check the diarrhea and relieve the pain, 
and various stimulants should be employed as 
symptoms may indicate. Rosenthal and Severn 
(Arch. exp. Path. Pharm., 1912, 67, 275) asserted 
that potassium hexatantalate is capable of fol- 
lowing the drug after its absorption and producing 
a non-toxic compound in the system. Dimercaprol 
(g.v.) decreased the mortality of animals poisoned 
with tartar emetic and several organic antimonial 
compounds (Eagle et al., J. Pharmacol., 1947, 89, 
196; Braun et al, ibid., Suppl., 1946, 87, 119). 
In all cases of suspected poisoning, the vomit, the 
passages from the bowels, and especially the urine 
should be reserved for chemical examination. The 
metal has been found in all the tissues of the body 
and is most abundant in the liver. 

Dose. — The dose of tartar emetic varies 
greatly according to the purpose for which it is 
employed. As a diaphoretic or expectorant it may 
be given 2 or 3 times daily in doses of 2 to 8 mg. 
(approximately %o to y& grain) by mouth. If 
used as an oral emetic, the dose is usually about 
30 to 60 mg. (approximately Y to 1 grain). 

As an intravenous injection in the treatment 
of protozoal or other infections it is usually given 
in the form of a 0.5 to 1 per cent solution in dis- 
tilled water, normal saline or dextrose-saline solu- 
tion. The drug is preferably taken from a freshly 
opened container and dissolved in a sterile solvent 
with aseptic precautions although sterilization may 
be accomplished by boiling gently for 5 minutes 
or by filtration; solutions should not be auto- 
claved (War Med., 1945, 7, 403, but see steriliza- 
tion method described under Injection of Anti- 
mony Potassium Tartrate). For doses employed 
see under Uses. The U.S. P. gives the usual in- 
travenous dose as 40 mg. (approximately Yz 
grain), in the form of 0.5 per cent solution, three 
times a week, with a range of dose of 20 to 100 
mg.; the maximum single dose is 100 mg., which 
should not be exceeded in 24 hours, and the total 
course should not exceed 1.5 to 2 Gm. 

Great care is required in injecting these solu- 
tions because of the danger of very troublesome 
cellulitis if any should escape into the surrounding 
tissues. 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

Off. Prep. — Compound Opium and Glycyr- 
rhiza Mixture; Compound Squill Syrup, NJ?. 

INJECTION OF ANTIMONY 
POTASSIUM TARTRATE. B.P. (LP.) 

Injection of Potassium Antimonyltartrate, Injectio 
Antimonii et Potassii Tartratis 

This injection is a sterile solution of antimony 
potassium tartrate in water for injection, the solu- 
tion being sterilized by heating in an autoclave 
(115° to 116° for 30 minutes) or by filtration 
-through a bacteria-proof filter. It is required to 



contain not less than 94.0 per cent and not more 
than 105.0 per cent of the labeled amount of anti- 
mony potassium tartrate. B.P. The LP. limits for 
Injection of Potassium Antimonyltartrate are the 
same. For uses and dose see the preceding mono- 
graph. 

ANTIMONY SODIUM TARTRATE. 
B.P. (LP.) 

Sodium Antimonyltartrate, Antimonii et Sodii Tartras 

Antimony Sodium Tartrate is made by the in- 
teraction of antimonious oxide and sodium acid 
tartrate. It contains not less than 96.0 per cent 
of C4H407SbNa, with reference to the substance 
dried to constant weight at 105°; the LP. specifies 
the same rubric but refers to the substance dried 
at 110°. 

I. P. Sodium Antimonyltartrate; Stibii et Natrii 
Tartras. 

Description and Standards. — Antimony so- 
dium tartrate occurs as colorless and transparent, 
or whitish, scales or powder, it is odorless, has a 
sweetish taste, and is hygroscopic. It dissolves in 
1.5 parts of water but is insoluble in alcohol. It 
responds to tests for sodium, antimony, and tar- 
trates. Not more than 2 ml. of either 0.01 N 
sulfuric acid or 0.01 A T sodium hydroxide is re- 
quired to bring the pH of a solution containing 
1 Gm. in 50 ml. to a pH of 4.5 (corresponding to 
a green color with bromocresol green). The 
arsenic limit is 8 parts per million; the lead limit 
is 5 parts per million. At 105° it loses not more 
than 6.0 per cent of its weight. 

Assay. — The assay is as described under Anti- 
mony Potassium Tartrate. Each ml. of 0.1 N 
iodine represents 15.44 mg. of C4H40-SbNa. B.P. 
The LP. assay differs from that of the B.P. only 
in minor details. 

Uses. — Antimony sodium tartrate is used for 
the same therapeutic purposes and in about the 
same dose as tartar emetic (see Antimony Potas- 
sium Tartrate). It has the advantages over the 
potassium salt of being considerably more soluble 
in aqueous media, and less irritant when injected. 

Doses. — As an expectorant, 2 to 8 mg. (ap- 
proximately %o to y& grain) ; as an emetic, 30 to 
60 mg. (approximately Y to 1 grain) ; as a proto- 
zoicide, 30 to 120 mg. (approximately Y to 2 
grains), by intravenous injection. |v] 

Storage. — Sodium Antimony Tartrate should 
be kept in a well-closed container. LP. 

INJECTION OF ANTIMONY SODIUM 
TARTRATE. B.P. (LP.) 

Injection of Sodium Antimonyltartrate, Injectio 
Antimonii et Sodii Tartratis 

This injection is a sterile solution of antimony 
sodium tartrate in water for injection, the solu- 
tion being sterilized by heating in an autoclave 
(115° to 116° for 30 minutes) or by filtration 
through a bacteria-proof filter. It is required to 
contain not less than 85.5 per cent and not more 
than 105.0 per cent of the labeled content of anti- 
mony sodium tartrate. B.P. The corresponding 
LP. limits for Injection of Sodium Antimonyl- 
tartrate are 95.0 and 105.0 per cent, respectively. 
For uses and dose see the preceding monograph. 



Part I 



Antipyrine 99 



SODIUM ANTIMONYLTHIOGLY- 
COLLATE. I.P. 

Stibii et Natrii Thio'glycollas 

/S.CH 2 .COONa 

Sbr 



\s.cH 2 .coo 



"Antimony Sodium Thioglycollate, dried at 
105° for 2 hours, contains not less than 96 per 
cent and not more than 101 per cent of C-tHtNaO-i- 
S2SD." U.S.P. XIV. The I.P. requires not less than 
35.5 per cent and not more than 38.5 per cent of 
Sb, calculated with reference to the substance 
dried at 100° for 4 hours. 

U.S.P. XIV. Antimony Sodium Thioglycollate. Sp. 
Tioglicolato de Sodio y Antimonio. 

Antimony sodium thioglycollate may be ob- 
tained by dissolving antimony trioxide in a solu- 
tion containing an equimolecular mixture of thio- 
glycollic acid and sodium thioglycollate; on evapo- 
rating the solution the salt is obtained. 

Description. — "Antimony Sodium Thioglycol- 
late occurs as a white or pink powder. It is odorless 
or has a faint mercaptan odor, and is discolored 
by light. Antimony Sodium Thioglycollate is 
freely soluble in water. It is insoluble in alcohol." 
U.S.P. XIV. 

Standards and Tests. — Identification. — (1) 
A transient blue color is produced on adding 1 
drop of diluted hydrochloric acid and 2 drops of 
a 1 in 100 ferric chloride solution to 3 ml. of a 1 
in 100 solution of antimony sodium thioglycol- 
late; on subsequently adding 1 drop of dilute am- 
monia T.S. (1 in 10) a deep red color is produced. 
(2) A white precipitate is produced on adding 1 
ml. of sodium hydroxide T.S. to 3 ml. of a 1 in 100 
solution of antimony sodium thioglycollate. (3) 
An orange precipitate is produced on passing hy- 
drogen sulfide into a solution of 100 mg. of anti- 
mony sodium thioglycollate in 2 ml. of water. 
Loss on drying. — Not over 2 per cent when dried 
at 105° for 2 hours. U.S.P. XIV. 

Assay. — About 600 mg. of antimony sodium 
thioglycollate, previously dried at 105° for 2 
hours, is dissolved in water containing hydro- 
chloric acid. After adding tartaric acid hydrogen 
sulfide is passed into the solution until precipita- 
tion of antimonous sulfide is complete; the pre- 
cipitate is successively washed with hydrogen sul- 
fide T.S., alcohol, ether, carbon disulfide, alcohol 
and ether, and dried to constant weight. The 
weight of sulfide multiplied by 1.913 represents 
the equivalent in terms of C4H4Na04S2Sb. U.S.P. 
XIV. The I.P. assay is practically identical. 

Uses. — This trivalent antimonial was reported 
by Randall (Am. J. Med. Sc, 1924, 168, 723) to 
be less toxic and more effective than antimony 
potassium tartrate in the treatment of granuloma 
inguinale (due to Leishmania donovani). He ad- 
vised at least 12 doses to be administered after 
the healing of the lesion. These findings were con- 
firmed by Patch and Blew (Can. Med. Assoc. J., 
1930, 23, 637) and by Senear and Cornbleet 
(Arch. Dermat. Syph., 1932, 25, 167). The com- 
pound has also been employed in treating kala- 
azar. It has proved to be less toxic than antimony 
thioglycollamide (see in Part II), but also less 



stable; as is generally true of the trivalent anti- 
monials, it is more toxic than the pentavalent 
derivatives. 

Dose. — From 50 to 100 mg. (approximately 
Yi, to 1^2 grains), dissolved in 10 to 20 ml. of 
sterile distilled water, may be given every third 
or fourth day, intravenously, subcutaneously or 
intramuscularly, for 15 or 25 doses. 

Storage. — Preserve "in tight, light-resistant 
containers." U.S.P. XIV. 

INJECTION OF SODIUM ANTI- 
MONYLTHIOGLYCOLLATE. I.P. 

Injectio Stibii et Natrii Thioglycollatis 

This injection is a sterile solution of sodium 
antimonylthioglycollate in water for injection; 
1.0 per cent of sodium citrate and 0.1 per cent of 
thioglycollic acid may be used for preservation; 
the solution is sterilized by heating in an autoclave 
(30 minutes at 115° to 116°) or by filtration 
through a bacteria-proof filter. The content of 
sodium antimonylthioglycollate (C4H404S2SbNa) 
is not less than 93.0 per cent and not more than 
107.0 per cent of the labeled amount. 

Storage. — Preserve preferably in single-dose, 
hermetically-closed containers, or in multiple- 
dose containers, protected from light. I.P. 

ANTIPYRINE. N.F. (I.P.) 

Phenazone, [Antipyrina] 



CH, 



./ 



CH, 



V3 



H 



The I.P. defines Phenazone as 2 : 3 -dimethyl- 1- 
phenyl-5-pyrazolone. 

I.P. Phenazone ; Phenazonum. Phenyldimethylpyra- 
zolonum; Pyrazolonum Phenyldimethylicum. Fr. Phenyl- 
dim^thylpyrazolone; Dimethyloxyquinizine. Ger. Phenyl- 
dimethylpyrazolon; Antipyrin. It. Fenil-dimetilisopira- 
zolone; Antipirina. Sp. Antipirina; Fenazona. 

Antipyrine was one of the first important syn- 
thetic medicinals ; it was introduced into medicine 
in 1887 as a result of research by Knorr directed 
toward the preparation of compounds possessing 
a quinine-like structure. Structually it is 1,5-di- 
methyl-2-phenyl-3-pyrazolone, named according to 
the standard nomenclature used in the United 
States, or l-phenyl-2,3-dimethyl-5-pyrazolone, if 
the tautomeric designation followed by the I.P. 
is used. Antipyrine may be classed as a derivative 
of pyrrole, C4H5N, found in coal tar, or more 
directly of pyrazole, which differs from pyrrole in 
having an atom of nitrogen in the number two 
position in place of — CH= in pyrrole. Pyrazole 
has the formula 

H 



HC 5 



2N 



HC- 



-CH 



and is isomeric with imidazole (the parent com- 
pound of histamine) ; in imidazole the tertiary 



100 Antipyrine 



Part I 



nitrogen is at the number three position (see under 
Histamine Phosphate). 

Synthesis of antipyrine may be effected in sev- 
eral ways. In one process phenylhydrazine, 
Cr,H.-.XH.XH2, is heated with ethyl acetoacetate, 
(CH 3 CO)CH 2 .COOC2H 5) to form the phenylhy- 
drazone of ethyl acetoacetate which loses a mole- 
cule of alcohol and forms a phenyl-methyl-pyra- 
zolone; this is methylated to antipyrine. Other 
syntheses use methylphenylhydrazine along with 
the enol form of ethyl acetoacetate or a halogen- 
crotonic ethyl ester without subsequent methyla- 
tion. 

Description. — "Antipyrine occurs as colorless 
crystals, or as a white, crystalline powder. It is 
odorless, has a slightly bitter taste, and its solu- 
tions are neutral to litmus paper. One Gm. of 
Antipyrine dissolves in less than 1 ml. of water, 
in 1.3 ml. of alcohol, in 1 ml. of chloroform, and 
in 43 ml. of ether. Antipyrine melts between 110° 
and 112.5°." N.F. , 

Standards and Tests. — Identification. — (1) 
A white precipitate forms on adding tannic acid 
T.S. to an aqueous solution of antipyrine. (2) A 
nearly colorless solution results on adding 100 
mg. of sodium nitrite to 12 ml. of a 1 in 100 solu- 
tion of antipyrine ; addition of 1 ml. of diluted sul- 
furic acid produces a deep green color. (3) A 
deep red color forms when one drop of ferric 
chloride T.S. is added to 2 ml. of a 1 in 1000 
solution of antipyrine; on adding 10 drops of sul- 
furic acid the color changes to a light yellow. (4) 
An orange-yellow precipitate forms on heating to 
boiling a mixture of 100 mg. antipyrine, 100 mg. 
vanillin, 5 ml. of distilled water, and 2 ml. of sul- 
furic acid. Loss on drying. — Not over 1 per cent, 
when dried at 60° for 2 hours. Residue on ignition. 
— Xot over 0.15 per cent. Heavy metals. — The 
limit is 20 parts per million. Completeness and 
color of solution. — Antipyrine dissolves com- 
pletely in an equal weight of cold distilled water, 
forming a colorless or not more than slightly yel- 
low (viewed transversely in a tube of 20 mm. 
diameter) solution. N.F. 

Incompatibilities. — Antipyrine is precipi- 
tated by most of the alkaloidal reagents, including 
potassium mercuric iodide, iodine, mercuric chlo- 
ride, and tannic acid. It partially decomposes 
calomel with the production of mercuric chloride 
and metallic mercury, the mixture darkening in 
color. This reaction is more rapid in the presence 
of sodium bicarbonate. With nitric acid it be- 
comes first yellow and later red. With nitrites 
such as ethyl nitrite, the green compound iso- 
nitrosoantipyrine is formed. With ferric salts a 
red color is produced. With copper salts a green 
color is produced. It liquefies or forms a soft mass 
when triturated with acetanilid, betanaphthol, 
chloral, phenol, phenyl salicylate, pyrogallol, so- 
dium salicylate, and thymol. 

Uses. — Locally antipyrine exercises an anes- 
thetic effect upon the nerve endings (see Sollman, 
J. A.M. A., 1918, 70, 216) and causes constriction 
of the superficial vessels. When ingested it acts 
as an analgesic and mild antipyretic. It has been 
used in measurement of body water in humans 
(see Soberman, /. Biol. Chem., 1949, 179, 31). 



Brodie and Axelrod (/. Pharmacol, 1950, 98, 
97) found antipyrine to be completely absorbed 
from the gastrointestinal tract and then to be 
evenly distributed throughout the body water. 
Only about 5 per cent of the drug is excreted in 
the urine, the remainder being metabolized in 
the body. 

Antipyrine is useful in medicine for the relief 
of pain, as neuralgias, myalgias, migraine and 
similar conditions. Its action is more prompt than 
that of aniline derivatives but it has lost favor 
to the less toxic and equally effective salicylates. 
It is less effective that aminopyrine but it is not 
known to have caused agranulocytosis. It has been 
used in certain spasmodic disorders, especially 
whooping-cough and epilepsy. Antipyrine has also 
been used as a mild antipyretic. 

In the treatment of various inflammatory con- 
ditions of the mucous membranes, as rhinitis and 
laryngitis, antipyrine is sometimes employed for 
its local anesthetic and vasoconstricting effects. 
For this purpose it is usually applied in strengths 
of from 5 to 15 per cent. It is occasionally used 
as a styptic in nasal hemorrhage, [v] 

Toxicology. — Antipyrine occasionally pro- 
duces unpleasant and sometimes alarming symp- 
toms, even after doses which would scarcely be 
regarded as excessive. The most common type of 
antipyrine poisoning is characterized by giddiness, 
tremor, free sweating with more or less collapse, 
a peculiar lividity with, in many cases, eruption 
of the skin most commonly morbilliform, but 
sometimes erythematous or urticarial. It causes 
less cyanosis than does acetanilid. After very 
large doses there may be drowsiness, deepening 
into coma, with dilatation of the pupil and epilep- 
tiform convulsions. Various irregular symptoms 
have been noted, such as amaurosis, pseudomem- 
branous stomatitis, swelling of the lips and tongue, 
laryngeal interference with the respiration. In 
some cases fever with nervous unrest and epilepti- 
form convulsions have been reported. 

The treatment of antipyrine poisoning is purely 
symptomatic. Circulatory stimulants, as ammonia, 
strychnine and atropine, should be given and the 
bodily temperature maintained by external appli- 
cation of heat. 

Dose. — The usual dose is 300 mg. (approxi- 
mately 5 grains); the I.P. gives the usual daily 
dose as 1 Gm. but indicates that as much as 1 Gm. 
at a time, and 4 Gm. daily, may be given. 

Storage. — Preserve "in tight containers." N.F. 

N.F. ANTISEPTIC SOLUTION. N.F. 

Liquor Antisepticus N.F. 

Dissolve 25 Gm. of boric acid in 650 ml. of hot 
purified water and allow the solution to cool. Dis- 
solve 0.5 Gm. of thymol, 0.5 Gm. of chlorothymol, 
0.5 Gm. of menthol, 0.1 ml. of eucalyptol, 0.2 ml. 
of methyl salicylate, and 0.01 ml. of thyme oil in 
300 ml. of alcohol. Mix the two solutions and 
add sufficient purified water to make 1000 ml. 
Keep the product in a tightly closed container 
during 2 hours or more, cool to 10° and filter at 
this temperature, using purified talc, if necessary, 
to clarify the product. Note. — Specially denatured 



Part I 



Apomorphine Hydrochloride 101 



alcohol Formula No. 38-B, prepared by adding 
6 pounds of boric acid and V/z pounds each of 
thymol, chlorothymol, and menthol to 100 gallons 
of ethyl alcohol, has been approved by the U. S. 
Treasury Department as being suitable for use in 
making this solution provided that adjustment is 
made for the quantities of formula ingredients in 
the denatured alcohol. N.F. 

Description. — "N.F. Antiseptic Solution is a 
clear, colorless liquid having an aromatic odor and 
a characteristic taste. It is acid to litmus paper. 
The specific gravity of N.F. Antiseptic Solution 
is about 0.971." N.F. 

Tests. — Quantitative test for boric acid. — The 
intensity of color produced on adding a turmeric 
solution to N.F. antiseptic solution is not less than 
that developed by adding the turmeric solution 
to a 2.3 w/v per cent solution of boric acid in a 
30 in 100 solution of alcohol in water. Antibac- 
terial test. — To 5 ml. of N.F. antiseptic solution 
is added 0.5 ml. of a standard culture of Staphylo- 
coccus aureus, both having been kept at 37.5° 
before mixing; after mixing, the liquid is also 
kept at this temperature. After exactly 5 minutes, 
a standard loopful of the mixture is transferred 
to each of 3 subculture tubes containing 10 ml. 
of standard culture medium and the tubes incu- 
bated at 37.5° for 48 hours, at the end of which 
time no bacterial growth appears in the tubes. 
For information concerning the standard culture, 
the standard culture medium, and the standard 
loopful reference should be made to the National 
Formulary. 

Alcohol Content. — From 26 to 29 per cent, 
by volume, of C2H5OH. N.F. 

Uses. — Although this preparation is an anti- 
septic it is too much to expect that its use in the 
mouth — which is the reason for its existence — will 
have material influence on the oral flora. As ordi- 
narily used by the laity, adequate time is not 
provided for the solution to exert its full effect; 
moreover, constant flow of saliva dilutes and 
washes away this and any other soluble antiseptic. 
But the solution is useful as a deodorant wash 
and is probably as valuable for this purpose as 
any proprietary solution on the market. The N.F. 
recommends that the wash be used undiluted. 

Storage. — Preserve "in tight containers." 
N.F. 

APOMORPHINE HYDROCHLORIDE. 
U.S.P., B.P., LP. 

Apomorphinium Chloride, [Apomorphinae 
Hydrochloridum] 



CH3.H 




cr.^Hp 



"Apomorphine Hydrochloride is the hydrochlo- 
ride of an alkaloid prepared from morphine." 



U.S.P. XIV. The B.P. requires it to contain not 
less than 83.0 per cent of C17H17NO2, calculated 
with reference to the substance dried to constant 
weight at 105°. The LP., like the U.S.P., has no 
assay requirement. 

I. P. Apomorphini Hydrochloridum. Apomorphinum 
Hydrochloricum; Chloretum Apomorphinicum; Apomorphi- 
num Chlorhydricum. Fr. Chlorhydrate d'apomorphine. 
Ger. Apomorphinhydrochlorid; Salzsaures Apomorphin. It. 
Cloridrato di apomorfina. Sp. Clorhidrato de apomorfina. 

Apomorphine, in the form of its sulfate, was 
first prepared by Arppe in 1845. The base is 
obtained by the elimination of the elements of a 
molecule of water from a molecule of morphine 
on heating the latter alkaloid in the presence of 
acids; a slight rearrangement of the molecular 
structure occurs simultaneously. In one process, 
apomorphine is prepared by heating morphine 
with eight times its weight of concentrated hydro- 
chloric acid in a suitable glass-lined autoclave 
for 2 or 3 hours at 140° to 150°. After evaporat- 
ing a portion of the free acid, the apomorphine 
hydrochloride crystallizes on cooling. The crude 
product is purified by recrystallization. Because 
of the ease of oxidation, exposure to air must be 
avoided as much as possible. Apomorphine may 
also be made from codeine, which is a methyl- 
morphine. 

Apomorphine base crystallizes with one mole- 
cule of water. It is soluble in alcohol, acetone, 
chloroform ; sparingly soluble in ether or benzene, 
and insoluble in petroleum benzin. According to 
Heiduschka and Meisner {Arch. Pharm., 1923) 
apomorphine sublimes in a vacuum. Apomorphine, 
in the form of its dimethyl ether, has been syn- 
thesized by Pschorr and Avenarius, and by Spaeth 
and Hromatka {Ber., 1929). 

Description. — "Apomorphine Hydrochloride 
occurs as minute, white or grayish white, glisten- 
ing crystals or white powder. It is odorless. It 
gradually acquires a green color on exposure to 
light and air. Its solutions are neutral to litmus. 
One Gm. of Apomorphine Hydrochloride dissolves 
in about 50 ml. of water and in about 50 ml. of 
alcohol. One Gm. dissolves in about 20 ml. of 
water at 80°. It is very slightly soluble in chloro- 
form and in ether." U.S.P. 

Standards and Tests. — Identification. — (1) 
A white or greenish white precipitate is formed on 
adding a slight excess of a 1 in 20 solution of 
sodium bicarbonate to 5 ml. of a 1 in 100 solution 
of apomorphine hydrochloride. On adding to this 
3 drops of iodine T.S. and shaking, an emerald 
green solution is produced. If this mixture is 
shaken with 5 ml. of ether and the layers are 
allowed to separate, a deep ruby red color is ob- 
served in the ether layer while the aqueous phase 
remains green. (2) A dark purple solution is 
formed when apomorphine hydrochloride is dis- 
solved in nitric acid. (3) A white precipitate, in- 
soluble in nitric acid, results when silver nitrate 
T.S. is added to a solution of apomorphine hydro- 
chloride; the precipitate soon turns black because 
of reduction to metallic silver. Addition of am- 
monia T.S. hastens the reduction. Water. — Not 
over 3.5 per cent, determined by drying 500 mg. 
of apomorphine hydrochloride at 105° for 2 hours. 



102 Apomorphine Hydrochloride 



Part I 



Specific rotation. — Not less than —49° and not 
more than —51°, determined in 0.02 N hydro- 
chloric acid containing the equivalent of 150 mg. 
of anhydrous apomorphine hydrochloride in each 
10 ml. Color of solution. — A solution of 100 mg. of 
apomorphine hydrochloride in 10 ml. of oxygen- 
free distilled water has no more color than a 
standard prepared as follows: to 1 ml. of a solu- 
tion containing 5 mg. of apomorphine hydrochlo- 
ride in 100 ml. of water are added, successively, 
6 ml. of distilled water, 1 ml. of a 1 in 2Q sodium 
bicarbonate solution, and 0.5 ml. of iodine T.S.; 
after standing 30 seconds 0.6 ml. of 0.1 N sodium 
thiosulfate is added and the solution is diluted to 
10 ml. Residue on ignition. — A negligible residue 
is obtained from 200 mg. of apomorphine hydro- 
chloride. Decomposition products. — Not more 
than a pale reddish color develops when 100 mg. 
of apomorphine hydrochloride is shaken with 5 ml. 
of ether. U.S.P. 

The B.P. requires'that the precipitate produced 
on addition of sodium bicarbonate be soluble in 
ether with the production of a purple solution, in 
chloroform to produce a blue solution and in 90 
per cent alcohol to form a green solution. The B.P. 
permits up to 5.0 per cent loss of weight on drying 
at 105°. The LP. limits loss of weight on drying 
also to 5.0 per cent, but the substance is dried 
to constant weight in a vacuum desiccator over 
sulfuric acid or phosphorus pentoxide. 

Incompatibilities. — Apomorphine hydrochlo- 
ride forms precipitates with sodium bicarbonate, 
tannic acid and most alkaloidal reagents. It is 
incompatible with oxidizing agents, forming col- 
ored solutions. 

Aqueous or alcoholic solutions of apomorphine 
are unstable, gradually acquiring a green color. 
Amy (/. A. Ph. A., 1931, 20, 1153) has shown 
that this change is not due to the action of light; 
it may be prevented by replacing the air in am- 
puls of the solution with carbon dioxide. The 
oxidation takes place more readily in alkaline 
solutions, and may be retarded by the addition of 
a little hydrochloric or acetic acid. The B.P. adds 
0.1 per cent w/v of sodium metabisulfite to delay 
decomposition of the official injection of apomor- 
phine hydrochloride. Solutions which have a 
green color are not to be used. 

Uses. — Apomorphine hydrochloride is a prompt 
and efficient emetic, producing results in 10 to 15 
minutes. Apomorphine induces emesis through a 
central action only. Eggleston and Hatcher 
(/. Pharmacol, 1912, 3, 551) located the site 
of action at the vomiting center in the medulla, 
but more recently Wang and Borrison {Arch. 
Neurol. Psychiat., 1950, 63, 928, and Proc. S. Exp. 
Biol. Med., 1951, 76, 335) described a chemo- 
sensitive trigger zone in the floor of the fourth ven- 
tricle which is sensitive only to emetic chemicals 
and does not respond as does the previously 
described vomiting center to electrical stimula- 
tion. Ablation of this zone produces in dogs tol- 
erance to apomorphine in doses as high as 1 Gm. 
intravenously (Gastroenterology, 1952, 22, 1). 

Therapeutic doses ordinarily have very little 
other action although in large doses, and occa- 
sionally in therapeutic doses, it has a hypnotic 
effect (Rosenwasser, Med. Rec, July, 1907). At 



times it causes euphoria, restlessness and tremors. 
There have been instances of serious depression 
and even death of feeble patients from the use of 
therapeutic doses. Although very large doses have 
a depressant action on the heart, it is probable 
that these unfortunate occurrences are due to 
the marked relaxation of the arteries and conse- 
quent fall of blood pressure which accompanies 
violent nausea. Apomorphine should not be used 
as an emetic in persons with enfeebled circulation 
such as occurs in cases of corrosive poisoning with 
peripheral vascular collapse, or narcosis due to 
opiates, barbiturates, ethyl alcohol, etc. 

Rovenstine and Hershey (Anesth., 1945, 6, 574) 
brought under control within 5 to 10 minutes the 
excessive central nervous system stimulation in 
patients with emergence delirium following gen- 
eral anesthesia by the slow intravenous or intra- 
muscular administration of 1.3 to 2 mg. of 
apomorphine hydrochloride in 10 ml. of isotonic 
sodium chloride solution. Similar results were 
obtained in patients with excessive muscular or 
psychic activity due to other causes. 

Apomorphine hydrochloride is useful in cases 
of poisoning or any other condition where it is 
desired promptly to empty the stomach. Its ad- 
vantages are its lack of irritation of the gastric 
mucosa, the smallness of dose which makes it 
possible to carry it in the form of a hypodermic 
tablet, and the promptness of its effect. In cases 
of narcotic poisoning, however, it frequently fails 
to act because of the depression of the vomiting 
center. When vomiting does not result from the 
first dose, it should not be repeated. In doses too 
small to act as an emetic, it is a nauseating 
expectorant in the early stages of acute bronchitis. 
One drawback to its wider use for this purpose is 
its instability in solution. White (Am. J. Obst. 
Gynec, 1952, 64, 91) found apomorphine in 
combination with scopolamine useful in producing 
analgesia and amnesia during labor. Subcuta- 
neous doses of 0.6 to 1.2 mg. appeared to poten- 
tiate scopolamine analgesia and the combined 
drugs decreased the need for inhalation anesthesia. 
No untoward effects were observed. 

Apomorphine hydrochloride is best used hypo- 
dermically; orally, its emetic action is not de- 
pendable and from 3 to 5 times the hypodermic 
dose is required. Nor is oral administration suit- 
able for the "conditioned reflex" method of treat- 
ing alcoholism (Quart. J. Stud. Alcohol, 1940, 1, 
501). It is absorbed sublingually (Walton, 
J.A.M.A., 1944, 124, 139), the emetic dose 
being from 6.5 to 10 mg. (approximately Vio to Vs 
grain), [v] 

The usual dose, subcutaneously, is 5 mg. (ap- 
proximately Yn grain) with a range of 1 to 5 mg. ; 
the maximum safe dose is 5 mg. and the total 
dose in 24 hours should seldom exceed 10 mg. 
The emetic dose for an infant is 1 mg. (approxi- 
mately Y60 gr.) hypodermically or 3 to 5 mg. 
orally (J. A.M. A., 1944, 124, 138). As an expec- 
torant, 1 to 2 mg. has been used subcutaneously. 

Storage. — Preserve "in small, tight, fight-re- 
sistant vials containing not more than 350 mg. 
The restriction of 350 mg. applies only to con- 
tainers from which prescriptions are filled." U.S.P. 



Part I 



Aprobarbital 103 



INJECTION OF APOMORPHINE 
HYDROCHLORIDE. B.P., I.P. 

Injectio Apomorphinae Hydrochloridi 

This injection is a sterile solution of apomor- 
phine hydrochloride in water for injection; it 
contains also 0.1 per cent w/v of sodium meta- 
bisulfite. The solution is sterilized by heating with 
a bactericide (0.2 per cent w/v of chlorocresol 
or 0.002 per cent w/v of phenylmercuric nitrate 
in the solution) to maintain a temperature of 
98° to 100° for 30 minutes, or by filtration 
through a bacteria-proof filter. B.P. The I.P. em- 
ploys 0.05 per cent of sodium pyrosulfite (meta- 
bisulfite). Neither pharmacopeia provides an as- 
say rubric. 

The injection should be protected from light; 
it may decompose on standing and if a green 
color develops the solution should be rejected. 

APOMORPHINE HYDROCHLORIDE. 
TABLETS. U.S.P. 

[Tabellae Apomorphinae Hydrochloridi] 

"Apomorphine Hydrochloride Tablets contain 
not less than 90 per cent and not more than 110 
per cent of the labaled amount of C17H17NO2.- 
HC1.^H 2 0." U.S.P. 

Sp. Tabletas de Clorhidrato de Apomorfina. 

Assay. — A representative sample of powdered 
tablets, equivalent to about 50 mg. of apomor- 
phine hydrochloride, is dissolved in water and, 
after adding sodium bicarbonate, extracted with 
peroxide-free ether to remove the apomorphine. 
After washing the combined ether extracts 20 ml. 
of 0.02 N sulfuric acid is added and the mixture 
agitated thoroughly; the excess of acid in the 
aqueous phase is titrated with 0.02 N sodium hy- 
droxide, using methyl red T.S. as indicator. Each 
ml. of 0.02 N sulfuric acid represents 6.256 mg. of 
Ci7Hi 7 N0 2 .HCl.^H 2 0. U.S.P. 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

Usual Size. — 5 mg. (approximately Vvi grain). 

APROBARBITAL. N.F. 

Allylisopropylbarbituric Acid, Allylisopropylmalonyurea 






{C ^2 



CH 2 CH=CH 2 



Alurate (Hoffmann-LaRoche) . 

Aprobarbital, which is 5-allyl-5-isopropylbar- 
bituric acid, may be prepared either by treating 
isopropylbarbituric acid with allyl halide at low 
temperature, according to German Patent 539,806 
(1920), or by heating isopropylallylmalonic acid 
with urea in the presence of sodium alcoholate, 
acidification of the product yielding the free acid, 
according to Swiss Patent 167,802 (1934). 

Description. — "Aprobarbital occurs as a fine, 
white, odorless crystalline powder having a 
slightly bitter taste. It is stable in air. A saturated 
solution is acid to litmus paper. Aprobarbital is 
very slightly soluble in cold water and is soluble 



in alcohol, in chloroform, and in ether. Apro- 
barbital melts between 140° and 141.5°." N.F. 

Standards and Tests. — Identification. — Tests 
(1) and (2) are practically identical with iden- 
tification tests (1) and (2) under Barbital and 
Cyclobarbital, while test (3) is the same as iden- 
tification test (3) under Cyclobarbital. Loss on 
drying. — Not over 1 per cent, when dried at 105° 
for 2 hours. Residue on ignition. — Not over 0.1 
per cent. Readily carbonizable substances. — A 
solution of 500 mg. of aprobarbital in 5 ml. of 
sulfuric acid has no more color than matching 
fluid A. N.F. 

Aprobarbital Sodium. — The sodium deriva- 
tive of aprobarbital is not officially recognized 
but it is included in N.N.R., where it is described 
as a white, microcrystalline, hygroscopic, odorless 
powder with a slightly bitter taste. It is very 
soluble in water, very slightly soluble in alcohol, 
and practically insoluble in ether. Aqueous solu- 
tions of aprobarbital sodium are alkaline to litmus. 
The N.N.R. states that the uses of aprobarbital 
sodium are the same as those of aprobarbital. 
The soluble sodium salt is intended for oral or 
rectal administration, particularly as preanesthesia 
medication; it may also be used in other cases in 
which large individual doses are required. 

Uses. — According to the classification by Fitch 
and Tatum (/. Pharmacol., 1932, 44, 325) apro- 
barbital is regarded as having intermediate dura- 
tion of action (see article on Barbiturates, in 
Part II, for general discussion). It is longer act- 
ing than amobarbital, but shorter than barbital 
(Tatum, Physiol. Rev., 1939, 19, 472). Actually 
the actions and uses of aprobarbital are similar 
to those of barbital but it is more active, hence 
the dosage is smaller. 

Aprobarbital has been reported to reduce the 
convulsive threshold to epileptogenic stimuli, as 
does phenobarbital and phenylhydantoin (Barany, 
Arch, internat. pharmacodyn. therap., 1947, 74, 
155). It is useful for general mild sedation, when 
it is administered orally. Aprobarbital has been 
reported to be useful as a rectal analgesic agent 
during labor, the sodium derivative being used 
for this purpose. Graham and Pettit {Am. J. Obst. 
Gyn., 1938, 35, 1023) reported that when ad- 
ministered in this manner they were able to pro- 
duce amnesia in 67 per cent of cases and partial 
amnesia in an additional 22 per cent. However, it 
tended to prolong duration of labor 2 to 5 hours. 
Hauch {Acta obst. et gynec. Scandinav., 1938, 18, 
164) previously had employed the drug as a basal 
amnesic agent in normal deliveries, and Huard 
et al. {Rev. med. franc, d' Extreme-Orient., 1938, 
16, 279) attested to intravenous use of the so- 
dium derivative preoperatively for basal sedation. 

Apparently the fairly long duration of sedation 
produced by aprobarbital is due to its slow elimi- 
nation by excretion and by degradation. Maynert 
and Van Dyke {Pharmacol. Rev., 1949, 1, 217) 
quote available literature to the effect that the 
compound is excreted by man to the extent of 
13 to 24 per cent of a single dose. Following re- 
peated administration it may continue to be 
excreted in urine for 3 to 5 days. Masson and 
Beland {Anesthesiology, 1945, 6, 483) reported 
that aprobarbital is partially metabolized, mainly 



1 04 Aprobarbital 



Part I 



in the liver. While the compound has not been 
found to be particularly toxic, Hoick et al. (J. A. 
Ph. A., 1950, 39, 630) reported development of 
tolerance to aprobarbital and cross-tolerance to 
Nostal. Jurgens (Arch. exp. Path. Pharm., 1951, 
212, 440) found that this drug did not produce 
any blood dyscrasias when administered to rabbits. 

Dose. — For mild sedation, 60 mg. (approxi- 
mately 1 grain) of aprobarbital at bedtime; in 
obstinate cases 130 mg. may be administered. 
For preoperative use the average dose, commonly 
of the sodium derivative, is 10 mg. per Kg. of 
body weight. One-third of the calculated dose is 
administered orally 10 to 12 hours (or the eve- 
ning) before surgery; the remainder being given 
2 hours before the operation. Since this is a large 
dose, care and judgment must be exercised in its 
use to avoid undesirably heavy sedation. 

Storage. — Preserve "in well-closed contain- 
ers." N.F. 

ARALIA. N.F. 

American Spikenard, Spignet, [Aralia] 

"Aralia consists of the dried rhizome and roots 
of Aralia racemosa Linne (Fam. Araliacece) ." 
N.F. 

American Spikenard is a perennial herb with 
several widely branched, unarmed, aerial stems 
which arise to the height of 1 to 1.8 meters and 
bear ternately to quinately compound leaves, 
each with broadly ovate leaflets having acumi- 
nate apices, cordate bases and doubly serrate 
margins. The flowers are small, greenish-yellow, 
and borne on panicles of umbels. The fruits are 
sub-globular, dark purplish to reddish-brown 
berries. It is indigenous to eastern North Amer- 
ica west to Minnesota and Missouri. The rhi- 
zomes and roots are collected in summer and 
autumn, cut into segments, the thicker rhizomes 
cut lengthwise and all carefully dried. Most of 
the commercial drug comes from Indiana, Mis- 
souri, North Carolina, Virginia, Washington and 
Illinois. 

Description. — "Unground Aralia. — The rhi- 
zome of Aralia is oblique, about 12 cm. long and 5 
cm. thick, somewhat flattened, tortuous, externally 
weak brown to weak yellowish orange, often scaly, 
somewhat annulately roughened, frequently cut 
longitudinally, and lighter-colored internally. The 
nodes are approximate, each having a prominent 
stem-scar about 3 cm. in width. The fracture is 
fibrous. Roots are numerous, of varying length 
and up to 25 mm. thick; externally furrowed, 
sometimes with transverse ridges and corky 
patches, pale red-purple to weak yellowish orange, 
usually cut longitudinally, the cut surfaces lighter- 
colored and spongy. The fracture of the cortex is 
short and of the wood short-fibrous. Aralia has 
an aromatic odor and a mucilaginous, pungent, 
and slightly acrid taste." N.F. For histology see 
N.F.X. 

"Powdered Aralia is light yellowish brown. The 
starch grains are simple or compound, spherical 
or angular, from 5 to 25 n in diameter. The ro- 
settes of calcium oxalate are from 30 to 70 n 
in diameter. The vessels have sclariform or reticu- 
late thickenings and simple or bordered pits. 



The powder also shows characteristic lignified 
cells from the hypodermis, 40 to 100 n in length 
and about one-half as broad, their walls showing 
simple pits (distinction from Aralia nudicaulis 
root)." N.F. 

Closely allied to the official species, both bo- 
tanically and therapeutically, are the A. nudi- 
caulis L. (American, False or Wild Sarsaparilla 
or Shot-bush) and the A. spinosa L. (Angelica 
Tree, Hercules Club or Prickly Elder) . The latter 
has sometimes been referred to, improperly, as 
"prickly ash" and has occurred as an adulterant 
of the true prickly ash, Xanthoxylum Ameri- 
canum. 

There appear to be no published reports of a 
phytochemical study of A. racemosa but Holden 
(Am. J. Pharm., 1880) found in A. spinosa a 
saponin to which he gave the name of araliin. It 
is probable that the official species owes whatever 
medicinal virtue it may possess to the presence 
of a small amount of a volatile oil. 

Standards and Tests. — Aralia contains not 
more than 5 per cent of attached stem-bases, nor 
more than 2 per cent of foreign organic matter 
other than stem-bases, and yields not more than 
2 per cent of acid-insoluble ash. A T .F. 

Uses. — Aralia has been used, especially in do- 
mestic practice, as an "alterative" similar to 
sarsaparilla. in the treatment of rheumatic, syphi- 
litic and cutaneous affections. In medical practice 
it was, at one time, occasionally employed in 
pectoral complaints but now is no longer pre- 
scribed. Its therapeutic value is extremely ques- 
tionable and it is official only because it is an 
ingredient of the compound white pine syrup. 

The N.F. assigns an average dose of 2 Gm. 
(approximately 30 grains). 

Off. Prep. — Compound White Pine Syrup. 
N.F. 

ARECA. N.F. 

Areca Nut, Betel Nut, [Areca] 

"Areca is the dried ripe seed of Areca Catechu 
Linne (Fam. Palmce). Areca yields not less than 
0.35 per cent of ether-soluble alkaloids calculated 
as arecoline." N.F. 

Betel Xut; Areca Nut; Areca Seed. Semen Areca:. 
Fr. Arec; Noix d'arec. Ger. Arekasamen ; Arekanusz; 
Pinangnusz. 

Areca Catechu is a tall palm tree, reaching a 
height of 30 to 50 feet, indigenous to the Malay 
Archipelago but now cultivated also in India, 
southern China, Philippine Islands and East 
Africa. Its fruit, borne in pendent panicles, is 
ovoid and from 2 to 3 cm. in diameter, and of 
an orange-yellow color, contains the seeds (or 
"nuts") embedded in a fibrous, fleshy envelope, 
and invested with a brittle shell which adheres 
to the exterior flesh. The seed, the betel nut 
of commerce, is of a rounded-conical shape, 
rather larger than a chestnut, externally of a 
deep brown, diversified with a fawn color, so as 
to present a reticulate appearance, internally 
brownish-red with whitish veins, very hard, of a 
feeble odor when broken, and of an astringent, 
somewhat acrid taste. 

Immense quantities of areca nut are consumed 



Part I 



Arecoline Hydrobromide 105 



in the East. The method used by betel chewers 
consists of smearing fresh leaves of the Betel- 
pepper (see Betel, Part II) with lime and cutch 
and placing slices of areca nut on the leaves, some- 
times with added flavoring. The entire mass is 
placed in the mouth, acting as a masticatory 
known by the name of Betel. The red color which 
this mixture imparts to the saliva and the excre- 
ments is caused by the areca nut, which is also 
powerfully astringent, and, by its internal use, 
tends to counteract the relaxation of bowels to 
which the heat of the climate so strongly pre- 
disposes. 

Description. — "Unground Areca. — Areca oc- 
curs as rounded-conical seeds, up to 3.5 cm. in 
length and up to 3 cm. in diameter. Externally it 
is weak reddish brown to light yellowish brown 
and is marked with a network of paler lines. 
Adhering portions of the silvery brittle endocarp 
and fibers of the mesocarp are usually found at 
the base of the seed. The seed is hard, the cut 
surface exhibiting a marbled appearance (rumi- 
nate endosperm) of brownish tissue alternating 
with whitish tissue. Areca has a slight odor and 
an astringent, slightly bitter taste." N.F. For 
histology see N.F.X. 

"Powdered Areca is weak reddish brown to 
light brown. It consists principally of fragments 
of the endosperm, with porous reserve-cellulose 
walls, irregularly thickened stone cells of the seed 
coat, a few aleurone grains up to 40 m. in diameter 
and a few oil globules. Starch is absent, and spiral, 
pitted and annular tracheids and vessels are few." 
N.F. 

Constituents. — Areca nut contains tannin, 
also gallic acid, a fixed oil, gum, a little volatile 
oil, lignin and several alkaloids. It yields its 
astringency to water, and in some parts of Hin- 
dustan an extract is prepared from it having the 
appearance and properties of catechu. A red 
coloring matter known as Areca red is extracted, 
probably resulting from the decomposition of a 
tannin. It is insoluble in cold water and ether, 
soluble in boiling water and alkaline liquids, from 
which it is precipitated by acids. 

From the seeds of areca Jahns isolated, in 1888, 
the alkaloids arecoline, arecaidine, arecaine and 
gavacaine; the second and third of these have 
been shown to be identical. To these have been 
added arecolidine, guvacoline and, possibly, a 
sixth alkaloid called isoguvacine. There is some 
basis for believing the last-named to be mainly 
arecaidine. Arecoline has been shown to be the 
methyl ester of arecaidine, and the latter has 
been identified and synthesized as 1 -methyl- A 3 - 
tetrahydropyridine-3-carboxylic acid. Guvacoline 
is now known to be the methyl ester of guvacine ; 
this, too, has been identified and synthesized as 
A 3 -tetrahydropyridine-3-carboxylic acid. For a 
further discussion of these alkaloids see Henry 
{Plant Alkaloids, 4th ed., 1949). 

Standards and Tests. — Areca contains not 
more than 2 per cent of adhering pericarp, nor 
more than 1 per cent of foreign organic matter, 
and yields not over 2.5 per cent of ash. N.F. 

Assay. — A sample of 8 Gm. of areca, in mod- 
erately coarse powder, is macerated with ether 
and ammonia; an aliquot representing 5 Gm. of 



drug is decanted after clarification, and most of 
the ether distilled off. The alkaloids in the con- 
centrated ethereal solution are extracted with 
15 ml. of 0.02 N sulfuric acid and the excess acid 
titrated with 0.02 N sodium hydroxide, using 
methyl red T.S. as indicator. Each ml. of 0.02 N 
sulfuric acid represents 3.104 mg. of alkaloids 
calculated as arecoline. N.F. 

Uses. — Areca nut owes its therapeutic uses 
almost entirely to the alkaloid arecoline, the other 
bases which it contains being relatively inert. 
For description of its effects see under Arecoline 
Hydrobromide. 

This drug is so far as we know, almost never 
used in human medicine but is employed, as a 
vermifuge, by veterinarians. Its use in veterinary 
medicine is described in Part III. The N.F. gives 
the dose for dogs as 2 to 4 Gm. (approximately 
30 to 60 grains) and for sheep as 4 to 8 Gm. 
(approximately 1 to 2 drachms) depending on the 
weight of the animal. 



ARECOLINE HYDROBROMIDE. N.F. 

Arecolinium Bromide, [Arecolinae Hydrobromidum] 

"Arecoline Hydrobromide is the hydrobromide 
of an alkaloid obtained from the dried ripe seed 
of Areca Catechu Linne (Fam. Palmaz) or pro- 
duced synthetically." N.F. 

Arecolinum Hydrobromicum; Arecolinae Bromhydras. 
Fr. Bromhydrate d'arecoline. Ger. Arekolinhydrobromid. 
Sp. Bromhidrato de arecolina. 

This alkaloid, discovered by Jahns in 1888, 
is obtained from areca nut (betel nut), which 
contains 0.3 to 0.6 per cent of arecoline. 
In a commercial process for preparing arecoline 
the powdered drug is extracted with alcohol, the 
solvent evaporated under vacuum, the syrupy 
residue dissolved in carbon tetrachloride and this 
solution extracted with dilute sulfuric acid, which 
removes the arecoline. The alkaloid may then be 
separated from the aqueous solution by alkaliniz- 
ing it and extracting with chloroform. The hydro- 
bromide provides the most suitable means for 
purifying the alkaloid by recrystallization. 

Arecoline has been synthesized by several dif- 
ferent methods. Mannich (Ber., 1942, 75B, 1480) 
prepared it starting with methylamine hydrochlo- 
ride, formaldehyde, acetaldehyde and water. Dan- 
kova et al. (see Chem. Abs., 1943, 37, 381) de- 
scribed what is said to be a commercially feasible 
synthesis starting with ethylene oxide (see also 
Ugryumov, Chem. Abs., 1941, 35, 3644). 

Arecoline has the structure of methyl 1,2,5,6- 
tetrahydro-1-methylnicotinate; it is a partially 
hydrogenated nicotinic acid derivative. The base 
is an oily, strongly alkaline, optically inactive 
liquid, boiling at about 209°. It is miscible with 
water, ether or chloroform and is volatile with 
steam. 

Description. — "Arecoline Hydrobromide oc- 
curs as a white, crystalline powder, or in the form 
of white crystals. It is odorless and has a bitter 
taste. It is affected by light. One Gm. of Areco- 
line Hydrobromide dissolves in about 1 ml. of 
water, in about 10 ml. of alcohol, and in about 
2 ml. of boiling alcohol. It is slightly soluble in 



106 Arecoline Hydrobromide 



Part I 



ether or chloroform. Arecoline Hydrobromide 
melts between 170° and 175°." N.F. 

Standards and Tests. — Identification. — (1) 
A 1 in 20 solution of arecoline hydrobromide re- 
sponds to tests for bromide. (2) A red-brown 
precipitate forms on adding iodine T.S. to a 1 in 
50 solution of arecoline hydrobromide; a yellow 
precipitate is produced by bromine T.S. Loss on 
drying. — Not over 1 per cent, when dried at 80° 
for 2 hours. Ash. — Not over 0.5 per cent. Acidity. 
— Not over 0.2 ml. of 0.1 N sodium hydroxide is 
required to neutralize 500 mg. of arecoline hydro- 
bromide, using methyl red T.S. as indicator. Sul- 
fate. — No turbidity or precipitate forms in 30 
seconds when 1 ml. of barium chloride T.S. is 
added to 10 ml. of a 1 in 100 solution of areco- 
line hydrobromide, acidulated with 5 drops of 
diluted hydrochloric acid. Other alkaloids. — No 
precipitate or turbidity is produced when ammo- 
nia T.S. or sodium hydroxide T.S. is added to a 
1 in 20 solution of arecoline hydrobromide (areco- 
line base is soluble in water). N.F. 

In a study of the stability of aqueous solutions 
of arecoline hydrobromide on sterilization, Schou 
(Dansk Tids. Farm., 1936, 10, 175) found that 
no hydrolysis occurred after heating for one hour 
at 100° but that autoclaving for 20 minutes 
at 120° decomposed 5 per cent of the areco- 
line. He found that solutions of the salt are 
stabilized by the addition of small amounts of 
hydrochloric acid. 

Uses. — Arecoline closely resembles pilocarpine 
in physiological action, both drugs stimulating 
structures innervated by postganglionic nerves 
(see the monograph in Part II on Parasympatho- 
mimetic Agents and Cholinesterase Inhibitors). 
Arecoline causes a marked increase of secretions, 
especially of the salivary gland, contraction of 
the pupil when instilled into the eye, increased 
intestinal peristalsis, constriction of bronchi, and 
a slowing of the heart and vasodilatation with 
resulting fall in blood pressure (Platz, Ztschr. 
exp. Path. Ther., 1910, 7; Jackson, /. Pharmacol., 
1914, 5, 479). Mentova (Farmakol. i Toksikol., 
1940, 3, 1) observed constriction of the coronary 
arteries in rabbits following administration of 
arecoline, acetylcholine or physostigmine. 

Arecoline has been employed to a small extent 
in the treatment of glaucoma. A 1 per cent solu- 
tion produces a marked reduction in the intra- 
ocular tension, but its effects are more transient 
than those of pilocarpine or physostigmine. It 
may cause considerable irritation of the cornea 
but apparently does not injure the continuity of 
the epithelium. 

Arecoline is a very potent taeniacide and ap- 
parently is also poisonous to the roundworm, 
but, according to Schueffner, has no influence on 
the hookworm (Arch. Schiffs-Tropen-Hyg., 1912, 
16, 569). Because, however, of its toxic systemic 
action it has been abandoned in human medicine 
but is still used by veterinarians, (v] 

Toxicology. — Excessive doses cause saliva- 
tion, vomiting, diuresis, coma and convulsions 
(Wachholz, Ztschr. ges. gerichtl. Med., 1932, 19, 
224). If ingested, gastric lavage and use of po- 
tassium permanganate are indicated. Atropine 



sulfate parenterally may minimize the effects of 
strong parasympathetic stimulation. The N.F. 
gives a dose lor horses of 30 mg. (approximately 
^2 grain) subcutaneously and for dogs of 1.5 mg. 
per kilogram of body weight (approximately %d 
grain per pound). 

Storage. — Preserve in "tight, light-resistant 
containers." N.F. 

ARECOLINE HYDROBROMIDE 
TABLETS. N.F. 

[Tabellae Arecolinae Hydrobromidi] 

"Arecoline Hydrobromide Tablets contain not 
less than 91 per cent and not more than 109 per 
cent of the labeled amount of CsHisNCte.HBr." 
N.F. 

Assay. — Not less than 20 tablets are allowed to 
disintegrate in distilled water, the mixture diluted 
to 200 ml., filtered, and an aliquot portion equiva- 
lent to about 0.3 Gm. of arecoline hydrobromide 
assayed by the Volhard method for bromide con- 
tent by adding a measured excess of 0.1 N silver 
nitrate and some nitric acid and titrating the ex- 
cess of silver nitrate with 0.1 TV ammonium thio- 
cyanate using ferric ammonium sulfate T.S. as 
indicator. Each ml. of 0.1 N silver nitrate repre- 
sents 23.61 mg. of C8Hi 3 N0 2 .HBr. N.F. 

Usual Sizes. — 8, 15. 30 and 60 mg. (approxi- 
mately %, x /i, Yz and 1 grain). 

ARNICA. N.F. 

Arnica Flowers, [Arnica] 

"Arnica consists of the dried flower head of 
Arnica montana Linne, known in commerce as 
European Arnica or of Arnica fulgens Pursh, 
Arnica sororia Greene and Arnica cordi folia 
Hooker, known in commerce as American Arnica 
(Fam. Compositor)" N.F. 

Wolf's Bane; Mountain Tobacco. Flores Arnica. Fr. 
Arnica; Fleurs d'araica. Ger. Arnikabliiten; Bergwurzel- 
blumen; Blutblumen; Engelblumen ; Gamsblumen. It. 
Arnica; Fiori di arnica. Sp. Arnica. 

Arnica montana L. is a perennial herb having 
a woody, brownish, horizontal rhizome, from 2 
to 10 cm. long, and 0.5 to 5 mm. thick, ending 
abruptly, and sending forth numerous slender 
fibers of the same color. The stem is up to 6 dm. 
in height, cylindrical, striated, glandular-hairy, 
and terminating in one, two, or three peduncles, 
each bearing a flower head. The radical leaves are 
oblanceolate, entire and ciliated; those of the 
stem, which usually consist of two opposite pairs, 
are elliptic oblong or lance-shaped. Both are 
bright green, and somewhat pubescent on their 
upper surface. The flower heads are orange-yellow. 

This plant is a native of the mountains and 
meadows of Europe. It has been introduced into 
England, and cultivated in northern gardens in the 
United States. The flowers, leaves and root are 
employed; but the flowers only are official. In 
the Swiss and German Pharmacopoeias the defini- 
tion of arnica flowers is restricted to the flowers 
separated from the receptacles, this being done 
as the latter contain the eggs or larvae of Trypeta 
arnicivora. On the other hand the Austrian Phar- 
macopoeia permits the use of the entire flower 



Part I 



Arnica 



107 



heads, but the receptacles containing larvae must 
be removed. 

The American species of Arnica recognized by 
the N.F. are Arnica fulgens, A. sororia and A, 
cordifolia. All of them are glandular-hairy, per- 
ennial herbs with slender horizontal rhizomes bear- 
ing basal rosettes of radical leaves from the 
centers of which arise one or more aerial stems 
bearing from 1 to 3 peduncles which terminate 
in showy flower heads of yellow to orange {A. 
julgens) ray and disk florets. A. julgens and A. 
sororia are native to southwestern Canada and 
western United States. A. cordifolia has a range 
from Alaska down the Rocky Mountains to New 
Mexico and Arizona, in the Sierra and Cascade 
ranges south to San Diego County, California. 

Arnica julgens Pursh or orange arnica is espe- 
cially characterized by possessing dense tufts of 
tawny hairs in the axils of the bases of its radical 
leaves of previous years which are attached to the 
rhizome, by its aerial, puberulent, glandular-hairy 
stem bearing from 4 to 6 pairs of cauline leaves, 
the upper pairs reduced and separated by a long 
internode from the lower pairs which are oblance- 
olate, entire or with a few teeth and by its flower 
head of dark orange to orange flowers. 

A. sororia Greene somewhat resembles the last 
species but its rhizome is less than half as thick 
with few or no tufts of hairs in the axils of the 
old attached radical leaves, its aerial stem bears 
4 to 5 pairs of cauline leaves, the two to three 
pairs near the base being oblanceolate, and its 
flower head bears yellow ray and disk florets. 

A. cordifolia Hooker or heart leaf arnica is char- 
acterized by having 2 to 4 pairs of cauline leaves, 
the basal and lower leaves being petiolate with 
slender, sometimes margined petioles as long as or 
exceeding the lamina, the latter varying from 
ovate to ovate-orbicular, cordate or lanceolate 
with cordate to truncate base and entire to 
coarsely toothed margin. Its flower heads are 
broadly turbinate to bell-shaped with yellow ray 
and disk florets. Its involucral bracts differ from 
those of the preceding species in being frequently 
irregularly toothed to laciniate along the margins. 
For details on the official Arnica yielding species 
and the gross structure and histology of their 
flower heads see the report of Youngken and 
Wirth, /. A. Ph. A., 1945, 34, 65. 

The flower heads of arnica are collected when 
fully expanded, the florets of European arnica 
being usually separated from their receptacles and 
carefully dried. American arnica flower heads are 
dried intact. European arnica has been imported 
into the U. S. A. from Germany, Belgium, Yugo- 
slavia, France and Italy. American arnica is being 
collected chiefly in the Rocky Mountain states, 
especially Montana and Wyoming, and also in 
the Dakotas. 

Description. — "Unground Arnica occurs as 
entire flower heads or as tubular and ligulate 
florets usually with some receptacles and invo- 
lucres. The heads are either hemispherical, tur- 
binate, or campanulate, up to 2.8 cm. in height. 
The receptable is flat to slightly convex (Arnica 
montana) or prominently convex (American 
Arnicas), deeply pitted, and covered with short 



hairs. The involucral bracts are lanceolate to 
elliptic oblong, those of A. cordifolia being fre- 
quently toothed or laciniate along the margins, 
light olive-green to weak reddish brown, puberu- 
lent and glandular-hairy, up to 25 mm. in length 
and from 1 to 3.5 mm. in width. The ligulate 
florets are yellow to moderate orange, pistillate, 
the ligulate corolla being up to 27 mm. in length, 
up to 6 mm. in width, its ligule usually 3-toothed 
and 7- to 12-nerved. The tubular florets are per- 
fect, goblet-shaped, yellow to yellowish orange, 
their stamens bearing 2 oblong-elliptic anther 
lobes united by an elongated triangular connective. 
The achenes are oblong to spindle-shaped, ap- 
pressed-hispid, longitudinally striate or dotted, 
3.5 to 7 mm. in length, brownish gray to light 
olive-brown, with a collar near the summit bearing 
a single circle of barbellate pappus bristles, a 
little longer than the achene. The odor is charac- 
teristic and agreeable. 

"Powdered Arnica is light yellowish brown to 
light olive-brown. The pollen grains are numerous, 
25 to 40 |x in diameter, spheroidal and spinose. 
The non-grandular hairs are of the following 
kinds : unicellular and uniseriate-articular, straight, 
curved or dagger-shaped, the uniseriate hairs up to 
9-celled, rarely 11-celled, some with short basal 
cells and elongated distal cell, and double hairs, 
the latter up to 384 n in length, mostly unequal 
in length of parts, with bifid summits, each with 
numerous pits on the dividing wall separating 
the 2 components, one of which is either 1- or 
2-celled. The glandular hairs are of the following 
kinds: with a unicellular stalk and a 1- to 2-celled 
head; or with a uniseriate or biseriate stalk and 
a 1-, 2-, or 4-celled head. The pappus bristles 
possess a multicellular axis and unicellular 
branches." N.F. 

Arnica flowers of commerce are not infre- 
quently admixed with and substituted by other 
composite flowers. Farwell states that the heads 
of Lapachis columnaris T. et G., a western com- 
posite, have been offered in large quantities for 
arnica. Hartwich has reported a sample of arnica 
adulterated with the flowers of the common dan- 
delion. Beilstein reported having found in one 
lot approximately 90 per cent of the flowers of 
Inula. The following flowers also have been used: 
Anthemis tinctoria, L., Calendula officinalis, L., 
Doronicum Pardalianches, L., Inula britannica, 
L., Scorzonera humilis, L., Heterotheca inuloides. 
The first three of these are distinguished by the 
fact that the achenes do not have any pappus. In 
Inula britannica the receptacle is naked and the 
ligulate flowers are four-nerved (for other char- 
acteristics see Ewing and Stitt, I. A. Ph. A., 1945, 
34, 151). In Scorzonera the flowers are all ligulate 
and the pappus is feather-shaped. In Heterotheca 
inuloides the florets have an inner long pappus 
and an outer short pappus. 

The rhizome (Arnica Radix) was formerly 
official and was described as follows : 

"Rhizome about 5 cm. long and 3 or 4 mm. 
thick; externally brown, rough from leaf-scars; 
internally whitish, with a rather thick bark, con- 
taining a circle of resin-cells, surrounding the 
short, yellowish wood-wedges, and large, spongy 



108 



Arnica 



Part I 



pith. The roots numerous, thin, fragile, grayish- 
brown, with a thick bark containing a circle of 
resin-cells. Odor somewhat aromatic; taste pun- 
gently aromatic and bitter." U.S.P., 1890. 

It appears to contain the same active con- 
stituents as the flowers. 

Standards. — Arnica contains not more than 
3 per cent of foreign organic matter, and not more 
than 2 per cent of acid-insoluble ash. N.F. 

Constituents. — In 1851 Bastick reported the 
presence of an alkaloid in arnica flowers but his 
findings have not been confirmed. The term 
arnicin has been applied to a variety of sub- 
stances which have been extracted from arnica 
but which are not related and most, if not all, of 
which are not pure principles. There is present 
about 0.5 per cent of a volatile oil, the most im- 
portant constituent of which is the dimethyl ether 
of thymohydroquinone. For further information 
on this oil, see Kondakow (/. pharm. chim., 1910, 
2, 79) and also Gildemeister and Hoffman, The 
Volatile Oils. There is present also in arnica 
flowers a colorless crystalline substance, known 
as arnidiol or arnisterin (Klobb, Pharm. Ztg., 
1905, 40, 846), for which Dieterle and Engelhard 
Arch. Pharm., 1940, 278, 225) proposed the name 
arnidendiol ; it is a triterpenediol found also in 
dandelion flowers {Zimmermann, Helv. Chim. 
Acta, 1941, 24, 393). Small amounts of angelic 
and formica acids have also been reported. From 
a petroleum ether extract of arnica flowers 
Dieterle and Fay {Arch. Pharm., 1939, 277, 65) 
isolated three crystalline substances, as yet in- 
completely identified. About 56 per cent of this 
extract consists of fatty acids, the composition 
of which is reported in their paper, along with 
other analytical data for the extract. 

Uses. — Arnica is rarely prescribed by physi- 
cians but has been used in domestic medicine as 
a counterirritant embrocation in the treatment of 
bruises and sprains, generally in the form of the 
tincture. It has also been used in the treatment 
of palsies and various other diseases, but little 
knowledge concerning its action is available. Forst 
{Arch. exp. Path. Pharm., 1943, 201, 242) re- 
ported that both aqueous and alcoholic extracts 
of A. montana contain, besides choline, two un- 
identified substances which affect the heart and 
vascular systems. 

Toxicology. — Arnica is an active irritant and 
is capable, when taken in an overdose, of produc- 
ing symptoms of violent toxic gastroenteritis, with 
considerable nervous disturbance, reduction or in- 
crease of pulse rate, and collapse. On the skin it 
may cause severe dermatitis. 

In a number of cases of severe or even fatal 
poisoning by arnica, the symptoms have been 
burning pains in the stomach, vomiting, choleraic 
diarrhea, giddiness, intense muscular weakness, 
dilated pupils, and finally complete insensibility 
and collapse (Schoenemann, Munch, med. Wchn- 
schr., 1938, 85, 787; Merdinger, ibid., 1469; 
Forst, ibid., 1939, 86, 145). In some cases the 
disturbances of the gastrointestinal tract have 
been absent, and the symptoms have been chiefly 
of cerebral origin. An ounce of the tincture lias 
produced serious, although not fatal, symptoms. 



An emetic, a saline purge, demulcent drinks and 
supportive and symptomatic measures are indi- 
cated for treatment of arnica poisoning. 

Arnica flowers have been given in a dose of 60 
to 200 mg. (approximately 1 to 3 grains). 

ARNICA TINCTURE. N.F. 

[Tinctura Arnicae] 

Arnica Flowers Tincture. Tinctura Arnica Florum. 
Fr. Teinture d'arnica. Ccr. Arnikatinktur. It. Tintura 
di arnica. Sp. Tintura de arnica. 

Prepare a tincture by Process P (see under 
Tinctures), from 200 Gm. of arnica, in moderately 
coarse powder, using a menstruum of 3 volumes 
of alcohol and 1 volume of water; macerate the 
drug during 48 hours, percolate slowly, repeat the 
maceration during 24 hours after 500 ml. of perco- 
late has been collected, then percolate until 1000 
ml. is collected. N.F. 

Alcohol Content. — From 63 to 69 per cent, 
by volume, of C2H5OH. N.F. 

This tincture is sometimes used externally as a 
mild counterirritant. The N.F. formerly assigned 
an average dose of 0.5 ml. (approximately 8 
minims) but it is rarely given internally (see 
under Arnica). 

Storage. — Preserve "in tight, light-resistant 
containers and avoid exposure to direct sunlight 
or to excessive heat." N.F. 

AROMATIC ELIXIR. U.S.P. 

Simple Elixir, [Elixir Aromaticum] 
Sp. Elixir Aromdtico. 

To 12 ml. of compound orange spirit add 
enough alcohol to make 250 ml. To this solution 
add 375 ml. of syrup in several portions, agitating 
vigorously after each addition; afterwards add, 
in the same manner, enough purified water to 
make 1000 ml. Mix 30 Gm. of talc with the 
liquid, filter the mixture through a filter wetted 
with diluted alcohol, returning the filtrate until a 
clear liquid is obtained. U.S.P. 

The only difficulty encountered in the prepara- 
tion of this popular vehicle is that of obtaining a 
clear filtrate, the colloidal dispersion of the drop- 
lets of volatile oils separated from compound 
orange spirit by dilution with a large proportion 
of water being largely responsible for the persist- 
ing turbidity. The high degree of fineness of many 
samples of talc is a contributing factor as is, ap- 
parently, also the large proportion of syrup which 
seems to delay flocculation as well as slow down, 
because of its viscosity, the rate of filtration. 
Several suggestions have been offered for im- 
proving the process — and the product — but none 
of these has been given official recognition. For a 
brief review of some of the recommendations for 
improving the formula see Saute and Lee {J. A. 
Ph. A., Prac. Ed., 1954, 15, 101), who proposed 
a modification in which a polyoxyalkalene nonionic 
solubilizer {Pluronic, Wyandotte Chemical Corp.) 
is added to the volatile oil component of the elixir 
and which avoids the need for filtering the elixir, 
since it is clear. 

Aromatic elixir, once very widely used as a 



Part I 



Arsenic 



109 



vehicle, still finds considerable use for this pur- 
pose ; it is employed in the formulation of several 
official elixirs and also in Iron and Ammonium 
Acetate Solution. 

Alcohol Content. — From 21 to 23 per cent, 
by volume, of C2H5OH. U.S.P. 

Storage. — Preserve "in tight containers." 
U.S.P. 

RED AROMATIC ELIXIR. N.F. 

Red Elixir, Elixir Aromaticum Rubrum 

Mix 14 ml. of amaranth solution with 986 ml. 
of aromatic elixir. N.F. 

Alcohol Content. — From 21 to 24 per cent, 
by volume, of C2H5OH. N.F. 

This vehicle is employed in the same way as 
aromatic elixir, differing from it only in color. 

Storage. — Preserve "in tight containers." N.F. 

ALKALINE AROMATIC SOLUTION 

N.F. 

Liquor Aromaticus Alkalinus 
Liquor Antisepticus Alkalinus. 

Mix 20 Gm. each of potassium bicarbonate and 
sodium borate with 100 ml. of purified water and 
add 100 ml. of glycerin; when effervescence ceases 
add the mixture to 500 ml. of purified water. Dis- 
solve 0.5 Gm. of thymol, 1 ml. of eucalyptol, 0.5 
ml. of methyl salicylate, and 14 ml. of amaranth 
solution in 50 ml. of alcohol; add the solution of 
salts to the alcoholic solution, agitating con- 
stantly, and finally add enough purified water to 
make 1000 ml. Allow the mixture to stand 24 
hours, shaking occasionally, then filter, using 10 
Gm. of purified talc, if necessary, to clarify the 
product. N.F. 

The effervescence which occurs in the prepara- 
tion of this solution is explained by the fact that 
sodium borate, which may be considered to repre- 
sent four molecules of boric acid only half neutral- 
ized by two molecules of sodium bicarbonate, is 
converted by glycerin to an acid-reacting complex 
capable of neutralizing two more molecules of an 
alkali such as potassium bicarbonate. The reac- 
tion is similar to that which occurs in the prepara- 
tion of compound sodium borate solution. 

Description. — "Alkaline Aromatic Solution is 
a clear, purplish red liquid, with an aromatic odor 
and taste. It is alkaline to litmus paper. Its specific 
gravity is about 1.04." N.F. 

Standard and Test. — Residue on ignition. — 
The residue from 10 ml. of alkaline aromatic solu- 
tion yields, on ignition, not less than 223 mg. and 
not more than 273 mg. of residue. N.F. 

Alcohol Content. — From 4 to 7 per cent, by 
volume, of C2H5OH. N.F. 

Uses. — This is a valuable substitute for a solu- 
tion of borax for washing the nasal or pharyngeal 
cavities. Its chief advantages are a mild alkalinity 
which helps to dissolve mucus and the fact that 
when diluted with an equal volume of water it is 
almost isotonic with the body fluids. For use in a 
dental spray bottle, it is diluted with 5 volumes of 
water. 

Storage. — Preserve "in tight containers." N.F. 



ARSENIC 

Arsenum 

As (74.91) 

Arsenium. Arsenicum. Fr. Arsenic. Ger. Arsen. It. 
Arsenico. Sp. Arsenico. 

Arsenic has been known since ancient times. 
It is sometimes found free in nature, but is gen- 
erally combined. Important ores include realgar, 
AS2S2; orpiment, AS2S3; and mispickel or arseni- 
cal pyrites, FeAsS. The element is usually pre- 
pared by heating the last-named ore in the absence 
of air, the arsenic subliming. When heated under 
pressure, arsenic can be melted; its melting point 
at 36 atmospheres is 814°. At atmospheric pres- 
sure it sublimes at about 450°. The element exists 
in several allotropic modifications, of which the 
steel-gray form, having a metallic luster and a 
density of about 5.7, is the most important. 

Two oxides of arsenic are known. Arsenous 
oxide or anhydride (white arsenic) is the trioxide, 
AS2O3, formed when the metal is heated in air. 
For further information on this substance, see 
under Arsenic Trioxide. The higher oxide is 
arsenic oxide (arsenic pentoxide) ; it is formed by 
the oxidation of the trioxide suspended in con- 
centrated nitric acid and heated. It is a white, 
amorphous mass which melts at a dull red heat. 
It is hygroscopic, absorbing water to form 
H3ASO4, orthoarsenic acid. Chemically, arsenic 
behaves as a metal only toward the halide acids; 
it does not form salts with the oxygen acids. Two 
classes of compounds are known in which arsenic 
is acid- forming : the arsenites derived from the 
trioxides, and arsenates, derived from arsenic 
pentoxide. In these compounds, arsenic closely 
resembles phosphorus. 

Arsenic added in small amount (1 in 1000) to 
lead increases its hardness. It is used for this pur- 
pose in making lead shot. Large quantities of 
arsenic compounds, especially those of lead and 
copper, are used in plant sprays as insecticides. 

Arsine is of interest because of its extraor- 
dinary toxic properties. Most metallic ores con- 
tain arsenic as an impurity. On contact with sul- 
furic acid such metals give off hydrogen arsenide, 
H3AS, or arsine, which is a colorless, inflammable 
gas, with a strong garlic-like odor, approximately 
2.7 times as heavy as air. Cases of poisoning have 
been reported arising from arsine generated in 
storage batteries, in smelting and other chemical 
industries (Spolyar and Harger, Arch. Ind. Hyg. 
Occup. Med., 1950, 1, 419; Morse and Setterlind, 
ibid., 2, 148; Josephson et al., ibid., 1951, 4, 43; 
Steel and Feltham, Lancet, 1950, 1, 108). The 
symptoms do not appear until some hours after 
exposure to the gas. They begin with headache, 
followed by nausea and vomiting and chills. The 
gas destroys red blood cells, in vivo. Acute hemo- 
lytic anemia with hemoglobinuria and jaundice 
develops. Neuropathy may develop. The only 
treatment, outside of removal from exposure, is 
that for acute hemolytic anemia — rest, inhalation 
of oxygen, blood transfusions, alkalinization of 
the urine. 

The detection of arsenic in forensic procedures 
is of great importance, several tests being of espe- 



no 



Arsenic 



Part I 



rial usefulness for such purposes. In the Reinsch 
test arsenic is detected by deposition, as copper 
arsenide, on metallic copper placed in a hydro- 
chloric acid solution of the sample to be tested; 
the identity of the arsenic compound is confirmed 
by heating in an ignition tube with access to air 
whereupon, if arsenic is present, a sublimate of 
crystals of arsenic trioxide is obtained in the cooler 
part of the tube. In the Marsh test the presence 
of arsenic is evidenced by treating the sample with 
nascent hydrogen (produced by the reaction of 
zinc and acid), by which arsenic is reduced to the 
gas arsine; this, when burned, decomposes to form 
arsenic which may be deposited on a cool surface 
as a brown to black mirror and which is soluble 
in sodium hypochlorite solution. The modified 
Gutzeit test, employed officially in testing for 
arsenic in medicinals, involves formation of arsine 
as in the Marsh test, but its presence is detected 
by the formation of a yellow to brown stain on 
mercuric bromide paper. Bettendorf's test, used 
chiefly in testing antimony compounds because 
the latter element does not interfere in the test, 
depends on the reduction of arsenic to the ele- 
mental state by stannous chloride ; the arsenic de- 
posits as a black precipitate. 

For medicinal uses of arsenic compounds see 
under Arsenic Trioxide and Carbarsone. 

ARSENIC TRIOXIDE. 

N.F., B.P., LP. 

Arsenious Acid, Arsenious Oxide, [Arseni Trioxidum] 

"Arsenic Trioxide, when dried at 105° for 2 
hours, contains not less than 99.5 per cent of 
AS2O3. Caution. — Arsenic Trioxide is extremely 
poisonous." N.F. The B.P. requires not less than 
99.8 per cent of AS2O3, the calculation being re- 
ferred to the substance as it is found. The LP. 
requires not less than 99.5 per cent of AS2O3, 
calculated with reference to the substance dried 
at 100° for 3 hours. 

LP. Arseni Trioxydum. Arsenous Acid Anhydride; 
Arsenic Sesquioxide; White Arsenic; "Arsenic." Acidum 
Arsenosum; Acidum Arsenicosum; Arsenicum Album; 
Anhydridum Arseniosum. Fr. Anhydride arsenieux ; Acide 
arsenieux; Arsenic blanc; Oxyde blanc d'arsenic. Ger. 
Arsenige Saure ; Arsentrioxyd; Arsenigsaureanhydrid. It. 
Anidride arseniosa; Acido arsenioso; Arsenico bianco. Sp. 
Anhidrido arsenioso; Trioxido de Arsenico; Acido 
arsenioso. 

Arsenic trioxide is found native in octahedral 
crystals, called arsenalite, or as monoclinic crys- 
tals, called clandetite. It is formed when arsenic 
or arsenical minerals are heated or roasted in the 
presence of air, and is a by-product in a number 
of metallurgic operations, as in the roasting of 
cobalt, copper, lead, nickel and tin ores. The 
arsenic trioxide condenses as an impure dust, and 
is purified by resublimation. 

Description. — "Arsenic Trioxide occurs as a 
white, odorless powder. It is stable in air. Arsenic 
Trioxide is slowly soluble in water. It is slightly 
soluble in alcohol and in ether, and freely soluble 
in glycerin. It is soluble in hydrochloric acid and 
in solutions of alkali hydroxides and carbonates." 
N.F. The B.P. describes it as a heavy white 
powder, or irregular lumps having a vitreous frac- 
ture, usually appearing stratified, and containing 
frequently both transparent and opaque varieties. 



The solubility is given as 1 part in 60 parts of 
water, the rate of solution depending upon the 
relative proportion of the two varieties present, 
and upon the degree of subdivision. 

Standards and Tests. — Identification. — A 
yellow mixture is produced when hydrogen sulfide 
T.S. is added to a 1 in 100 solution of arsenic tri- 
oxide; addition of a few drops of hydrochloric 
acid to the mixture precipitates yellow arsenic tri- 
sulfide. Loss on drying. — Not over 1 per cent, 
when dried at 105° for 2 hours. Residue on igni- 
tion. — Not over 0.1 per cent. Foreign substances. 
— 1 Gm. of arsenic trioxide dissolves completely 
in 10 ml. of ammonia T.S., with the aid of gentle 
heat, or leaves only a very light trace of white, 
insoluble material. N.F. 

The N.F. has no requirement concerning the 
fineness of powder. The U.S. P. X required that 
when powdered arsenic trioxide was administered 
in solid form the particles should not be greater 
than 0.0125 mm. in diameter. This specification 
would appear to be a desirable one, as it has been 
demonstrated that the absorption of arsenic from 
the alimentary tract is largely dependent on the 
fineness of the powder administered. 

Assay. — About 200 mg. of arsenic trioxide. 
previously dried at 105° for 2 hours, is dissolved 
in boiling water with the aid of sodium hydrox- 
ide T.S.; the solution is neutralized with diluted 
sulfuric acid, sodium bicarbonate is added, and 
the mixture is titrated with 0.1 A 7 iodine, using 
starch T.S. as indicator. In the assay, the arsenic 
is oxidized from the trivalent to the pentavalent 
state. Each ml. of 0.1 N iodine represents 4.946 
mg. of AS2O3. N.F. 

Uses. — In sufficient concentration all of the 
official preparations of arsenic are violent. irritants 
or escharotics. Taken internally in a dose of 100 
mg. or more they are exceedingly poisonous to 
both man and the lower animals. Arsenic, in 
soluble forms, is absorbed from the mucous mem- 
branes and skin and from sites of parenteral ad- 
ministration; it is distributed by the blood to all 
parts of the body, being detectable in the hair in 
about two weeks and for many months thereafter. 
It is found in the urine within a few hours after 
oral or parenteral administration and excretion 
continues for several weeks; because of its slow 
elimination, cumulative action is an important 
consideration. For details of a recent study on 
the storage and metabolism of arsenic in tissues 
see Ewing et al. {Texas Rep. Biol. Med., 1950, 
8, 556; 1951, 9, 27). 

The local application of arsenic produces mild 
irritation followed, after prolonged or repeated 
application, by necrosis of tissue. Because rapidly 
proliferating tissue appears to be most sensitive 
to this action of arsenic it has been used in a 
variety of mixtures ("cancer paste") for the local 
treatment of neoplastic growths but its lack of 
penetration into the deeper portions of the tumor 
makes it ineffective (see U.S.D., 21st ed., p. 188). 
Arsenic is a marked capillary poison, causing 
dilatation and abnormal permeability with a re- 
sulting loss of protein and other blood plasma 
constituents into the tissues. Edema is a common 
manifestation of arsenic poisoning. The blood 
pressure does not decrease until the arterioles are 



Part I 



Arsenic Trioxide 



111 



similarly damaged or the loss of blood volume be- 
comes significant. The myocardium is also de- 
pressed. Hyperemia of the gastrointestinal tract 
follows either oral or parenteral administration 
and may promote the formation of digestive se- 
cretions and the absorption of food. Slightly larger 
doses, however, cause severe irritation of the 
mucosa with the formation of submucosal blebs 
and the loss of blood plasma into the lumen of 
the bowel accompanied by increased peristalsis, 
a condition which results in "rice water" stools 
which may become bloody. Vomiting is frequent. 
In addition to its action on the capillaries of the 
glomeruli of the kidney, arsenic produces necrosis 
and degeneration of the tubules. Oliguria, albu- 
minuria, hematuria and cylindruria are observed 
and the clinical features of the nephrotic stage of 
glomerular nephritis may develop. Vasodilatation 
in the skin causes a "healthy" flush but, except in 
minimal doses, abnormal proliferation of the skin 
and other epidermal structures such as the hair 
and nails results. Peripheral neuropathy involv- 
ing both the sensory and the motor elements is a 
frequent result of large doses of arsenic or pro- 
longed exposure to smaller amounts. Cell forma- 
tion in the bone marrow is temporarily stimu- 
lated, then depressed to a degree dependent on the 
amount of arsenic; this involves both the red and 
the white blood cell-forming elements. In toxic 
doses arsenic increases the excretion of nitrogen 
due to its destructive action on the tissues of 
many organs of the body. For many years small 
doses of arsenic were employed as a tonic in con- 
valescent, neurasthenic, and malnourished pa- 
tients. Although a decreased excretion of nitrogen 
and of carbon dioxide has been reported, the 
cumulative action of arsenic has made it clinically 
impractical to avoid toxic effects and this use of 
arsenic is no longer popular. Early toxic effects 
may even simulate clinical improvement through 
a flushed skin, minimal edema, and possibly im- 
proved absorption induced by hyperemia of the 
intestinal tract. 

The apparent tolerance to arsenic developed by 
the mountaineers of Styria and the Tyrol who are 
able to consume large quantities is explicable on 
the basis of the insolubility and poor absorbability 
of the form ingested (/. Pharmacol., 1922, 20, 
181); no tolerance has been observed following 
parenteral administration of arsenic compounds. 

Although arsenic is a protoplasmic poison it 
does not actively precipitate protein and in con- 
centrations and forms which are not caustic its 
action is slow. The theory that arsenic interferes 
with essential protoplasmic oxidation and reduc- 
tion processes has long been held. Voegtlin and 
his associates {Pub. Health Rep., 1923, 38, 1882; 
/. Pharmacol., 1930, 39, 347) produced evidence 
that arsenic combines with the sulfhydryl ( — SH) 
groups in cells to prevent normal oxidative proc- 
esses both in vitro and in vivo. They found that 
the administration of substances with free sulfhy- 
dryl groups had prophylactic and therapeutic 
value against the action of arsenic on mammals 
and on protozoa. Eagle and his associates (/. Phar- 
macol, 1938, 64, 164 and 1939, 66, 10 and 436; 
Am. J. Syph. Gonor. Ven. Dis., 1939, 23, 310) 
and Kolmer and his colleagues (Am. J. Syph. 



Gonor. Ven. Dis., 1940, 24, 201) have also pre- 
sented information on the mechanism of the action 
of arsenic. Eagle et al. (Fed. Proc, 1946, 5, 175) 
and others (Science, 1945, 102, 601) have re- 
ported that the dithiol compound, dimercaprol 
(q.v.), is far superior to the monothiol com- 
pounds such as glutathione, methionine (Peters 
et al., Quart. J. Med., 1945, 14, 35), etc. in the 
prevention and treatment of arsenical poisoning 
in man, animals, and protozoa. Arsenic inhibits 
the action of cellular enzymes (Maver and 
Voegtlin, Am. J. Cancer, 1937, 29, 333) and pre- 
vents mitosis and other nuclear functions. The 
hazard of epithelioma of the skin in occupations 
with exposure to arsenic is presented by Hueper 
(Occup. Med., 1948, 5, 157) and Hill and Faning 
(Brit. J. Ind. Med., 1948, 5, 1). 

In dentistry, equal parts of arsenic trioxide and 
cocaine hydrochloride made into a stiff paste with 
creosote is used in root canals to destroy ("kill") 
the nerve. Utilizing the radioactive isotope, As 76 , 
Gotte et al. (Ztschr. Naturforsch., 1951, 6b, 274) 
showed that the arsenic diffused into the dentin 
to a considerable extent, where it may cause latent 
degenerative changes. 

Although the inorganic forms of arsenic are 
highly toxic to many protozoa they are less suc- 
cessful in the treatment of parasitic infections 
than the organic forms, because the latter can be 
given in so much larger doses without danger to 
the host (see Carbarsone). To what action arsenic 
owes its value in pulmonary diseases is unknown 
but there has been a clinical impression that in 
chronic bronchitis, especially of the aged, and in 
asthma, it is beneficial. With the advent of liver 
therapy, arsenic was abandoned in pernicious 
anemia. 

When preparations of arsenic are given for their 
tonic effect alone, they should be used in doses so 
small as not to cause any general symptoms (see 
also Potassium Arsenite Solution). Mixtures of 
arsenic with nux vomica, quinine and other "bit- 
ters" are less popular than formerly. To avoid 
gastrointestinal irritation, pain and diarrhea as 
much as possible, the remedy should be given 
after meals. S 

Toxicology. — The specific symptoms of ar- 
senicalism are a general disposition to edema, 
especially of the face and eyelids, a feeling of 
stiffness in these parts, itching of the skin, tender- 
ness of the mouth, loss of appetite, and uneasi- 
ness and sickness of the stomach, usually with 
diarrhea. The symptoms of chronic arsenic poison- 
ing are so protean as to defy detailed description ; 
most of them fall into 3 groups. First, those due 
to irritation of the gastrointestinal tract, nausea 
and diarrhea; or, when the arsenic has been in- 
haled, symptoms of laryngitis and bronchitis. 
Second, when used continuously over long periods 
of time, even in doses too small to cause the cus- 
tomary symptoms of arsenicalism, the drug may 
give rise to alterations in the skin. The most im- 
portant of these are peculiar dryness and a tend- 
ency to the overgrowth of keratin as shown by 
the formation of warts, ridges on the finger nails 
or coarseness of the hair. In the diagnosis of sus- 
picious cases of arsenic poisoning, chemical ex- 
amination of the hair or finger nails for arsenic 



112 



Arsenic Trioxide 



Part I 



is valuable (Althausen and Gunther, J.A.M.A., 
1929, 92, 2002; Hamori, Deutsche med. Wchn- 
schr., 1941, 67, 628). In some instances the in- 
ternal use of arsenic causes a rash not unlike that 
of measles attended, as in that affection, with 
catarrhal symptoms. Sometimes salivation is pro- 
duced, and occasionally the hair and nails fall off. 
Third, the group of cases in which peripheral 
neuritis is the outstanding manifestation. This 
neuropathy may involve either motor or sensory 
elements with paralysis, paresthesia or pain. Im- 
paired vision has resulted. Any of these symptoms 
call for the discontinuance of arsenic therapy. 

Arsenic is still one of the most commonly used 
poisons for criminal purposes. Arsenic compounds 
are used as insecticides and rodenticides and acci- 
dental human poisoning occurs. The symptoms of 
acute poisoning, which generally do not appear 
for a period of from one-half to one hour after 
the ingestion of the poison, are somewhat varied 
in different cases. The most frequent are; pain in 
the epigastrium; vomiting, the vomitus being 
occasionally bloody, more commonly not; profuse 
serous purging; great thirst; rapid, weak pulse; 
prostration and restlessness, sometimes with de- 
lirium and convulsions. Any or all of these symp- 
toms, however, may be lacking, death occasionally 
taking place with no prodromal symptoms except 
heart failure or stupor. At post-mortem examina- 
tion there will be found evidence of inflammation 
of the alimentary canal and of the kidney and fre- 
quently fatty degeneration in various of the in- 
ternal organs. In the series of cases of arsenic 
poisoning reported by Lawson {J. A.M. A., 1925, 
85, 24) enlargement of the liver was observed 
in more than half of the cases and enlargement 
of the spleen in about one-quarter. Death usually 
occurs in the fatal cases within 48 hours (few 
hours to several weeks). 

The diagnosis of acute arsenical poisoning is 
sometimes impossible without chemical examina- 
tion. For the methods of detecting arsenic in the 
human body, see U.S.D., 19th ed., p. 202 and 
Morris and Calvery, Ind. Eng. Chem., Anal. Ed., 
1937, 9, 447. It should be remembered that even 
after the post-mortem injection of arsenic, as in 
the use of some embalming fluids, the poison may 
be diffused throughout the entire body. 

In the treatment of poisoning by arsenic, it is 
of the utmost importance to prevent the absorp- 
tion of the drug, because after the poison has once 
entered the system, it is difficult to mollify its 
baneful effects. The most important method of 
preventing absorption is the mechanical evacua- 
tion of the stomach — unless nature has already 
done so by vomiting — either by use of the stomach 
tube with large amounts of warm water or milk, 
or by means of a promptly acting emetic such as 
2 Gm. (approximately 30 grains) of zinc sulfate 
in water. It is to be remembered that the poison 
may remain in the stomach for long periods, espe- 
cially if it has been taken in solid form, and 
cleansing of the stomach is advisable even if the 
patient is not seen immediately after the ingestion. 
Prior to evacuation of the stomach, the inges- 
tion of a precipitant or adsorbent to decrease the 
amount of dissolved arsenic available for absorp- 
tion seems rational. Formerly, a freshly precipi- 



tated ferric hydroxide suspension {Magma Ferri 
Hydroxidi, U.S. P. XI) was advocated (see U.S.D., 
24th ed., p. 105), this being prepared by adding 
a solution of ferric sulfate to a suspension of 
magnesium oxide in water or to magnesia magma. 
A quick substitute may be prepared by adding 
any alkaline hydroxide solution to the solution of 
any available soluble ferric salt. Evacuation of 
the intestines by a saline purgative such as mag- 
nesium sulfate should follow removal of the 
gastric contents. Loss of fluid and electrolytes 
should be corrected by intravenous injection of 
isotonic sodium chloride solution. 

As soon as the diagnosis of arsenic poisoning 
has been made, whether it is in an early or a late 
stage, Dimercaprol Injection (q.v.) should be 
given intramuscularly in a dose of 2.5 to 3 mg. 
of dimercaprol per kilo of body weight and re- 
peated every 4 hours for 3 or 4 doses; if neces- 
sary, single daily doses should be continued for 
several days (Bull. U. S. Army M. Dept., 1945, 
Xo. 88, 13). In acute and severe cases the inter- 
val between the first and second doses should be 
shortened to 2 hours. Eagle reported the urinary 
excretion of arsenic to be increased as much as 
100 times during 1 to 2 hours after each injection, 
with an incidence of only 1 per cent of untoward 
reactions. The reactions usually occur within 15 
to 30 minutes after the injection and consist of 
sensations of constriction in the throat, oppression 
in the chest, burning of the lips, lacrimation and 
congestion of the conjunctiva, local tenderness, 
restlessness and nervousness, sweating of the 
hands, mild nausea and vomiting, headache and a 
transient rise in blood pressure. Since the intro- 
duction of dimercaprol the use of sodium thio- 
sulfate routinely in the treatment of arsenical 
poisoning has been abandoned. Evidence for its 
value was never clear (J.A.M.A., 1942, 120, 124). 
Although Ayres and Anderson (J.A.M.A., 1938, 
110, 886) reported that sodium thiosulfate in- 
creased the urinary excretion of arsenic, Muir, 
Stenhouse and Becker (Arch. Dermat. Syph., 
1940, 41, 308) and other observers found no such 
action. 

The subsequent treatment consists in the ad- 
ministration of mucilaginous drinks, and the treat- 
ment of symptoms as they arise. An adequate 
intake of protein, carbohydrate and vitamins, 
orally or parenterally, is important. Conva- 
lescence is generally long and distressing; usually 
dyspeptic symptoms mark the presence of gastro- 
intestinal inflammation or even ulceration, while 
not rarely violent neuralgic pains, with loss of 
power, wasting of the muscle, and other trophic 
changes, show that a peripheral neuritis has been 
produced. 

Chronic arsenical poisoning is a not infrequent 
— but often unrecognized — result of the continued 
absorption of small amounts of the element 
through either the alimentary or the respiratory 
tract. It has occurred from the inhalation of the 
dust of arsenical pigments, from the ingestion of 
contaminated foods and from the prolonged use 
of medicinal preparations. The arsenical dyes are 
not used today for coloring foods, but vegetables 
and fruit are occasionally injurious from the resi- 
due of agricultural insecticides. A serious epi- 



Part I 



Asafetida 



113 



demic in Manchester, England, in 1900 was traced 
to contaminated sulfuric acid used in making glu- 
cose. The increasing use of arsenic sprays, espe- 
cially lead arsenate, in agriculture constitutes a 
menace to public health (Calvery, J. A.M. A., 1938, 
111, 1722). Some of these foods enter our mar- 
kets today containing enough arsenic to be po- 
tentially dangerous. 

Dose, of arsenic trioxide, 1.5 to 3 mg. (ap- 
proximately y±o to V20 grain) . 

Storage. — Preserve "in well-closed containers." 
N.F. 

Off. Prep.— Arsenic Trioxide Tablets, N.F.; 
Potassium Arsenite Solution, N.F., B.P. 

ARSENIC TRIOXIDE TABLETS. N.F. 

Arsenous Acid Tablets, [Tabellae Arseni Trioxidi] 

"Arsenic Trioxide Tablets contain not less than 
92.5 per cent and not more than 107.5 per cent of 
the labeled amount of AS2O3." N.F. 

Assay. — A representative sample of powdered 
tablets, equivalent to about 60 mg. of arsenic tri- 
oxide, is boiled with water and then hydrochloric 
acid and chloroform are added and the mixture 
allowed to stand two hours, with occasional agi- 
tation. The mixture is then titrated with 0.02 M 
potassium iodate until the purple color which de- 
velops in the chloroform layer during the first 
part of the titration is discharged. In the reaction 
with iodate the arsenic is oxidized to the pentava- 
lent state while the iodate is reduced to iodine, 
which gives to chloroform the purple color; 
further addition of iodate oxidizes the iodine to 
iodine monochloride, IC1, in which iodine has a 
valence of +1. One mole of arsenic trioxide is 
equivalent to one mole of potassium iodate; ac- 
cordingly, 1 ml. of 0.02 M potassium iodate repre- 
sents 3.956 mg. of AS2O3. N.F. 

Usual Size. — 2 mg. (approximately Vao grain). 

ASAFETIDA. N.F. 

Gum Asafetida, [Asafoetida] 

"Asafetida is the oleo-gum-resin obtained by 
incising the living rhizome and roots of Ferula 
Assa-fcetida Linne, Ferula rubricaulis Boissier, 
and of Ferula jcetida (Bunge) Regel, and prob- 
ably of other species of Ferula (Fam. Umbel- 
lifer cb.)" N.F. 

Gum Asafetida; Devil's Dung. Asa Foetida; Gum- 
miresina Asafoetida. Fr. Asa fcetida. Ger. Asant ; Teufels- 
dreck. It. Assa fetida. Sp. Asafetida. Pers. Ungoozeh. 
Arab. Hilteet. Ind. Hing. Afgh. Angusakema. 

Asafetida appears to have been introduced into 
European medicine by the Arabian physicians. It 
was in use in continental Europe during the Mid- 
dle Ages. It has long been recognized in the U.S. P. 
but was deleted from the twelfth revision and 
admitted to the N.F. VII. The plants from which 
it is obtained are natives of western Afghanistan 
and eastern Persia. 

Ferula Assa-fcetida was first described from 
actual observation by H. Falconer, who found 
it near Kashmir, and it has long been successfully 
cultivated in the Edinburgh Botanical Gardens. 
It is distinguished from allied plants by the greater 
height of the stem (6 to 10 feet), and by the 
numerous stem leaves furnished with broad sheath- 



ing petioles. The flowers are pale yellow, and the 
oval fruit thin, flat, foliaceous, and reddish brown, 
with pronounced vittae. It yields a milky juice 
having a powerful odor of asafetida. 

Ferula fcetida is a coarse umbelliferous plant, 
growing from 5 to 7 feet high, with a large fleshy 
root, the crown of which is covered with coarse 
bristly fibers, and gives origin to large bipinnate 
radical leaves and a nearly naked stem which has 
only a few bipinnate leaves and ends at the top 
in very numerous umbels. This plant was first dis- 
covered in the sandy desert near the sea of Aral, 
by Lehmann, in 1844. Bunge found it in Persia 
about twenty years later. It would seem to be 
native all through Afghanistan. 

Ferula rubricaulis Boissier is mentioned as a 
source of galbanum in the Pharmacographia, 2nd 
ed., and in Bentley and Trimen's Medicinal Plants, 
but Holmes, studying Kotscky's specimen in the 
British Museum, classifies it with the asafetida 
plants partly because its fruit possesses an allia- 
ceous taste which is wanting in the fruit of the 
galbanum and partly because Boissier placed this 
species in his Sect. Scorodosma along with Ferula 
Assafcetida and F. alliacea, both of which are con- 
sidered as sources of asafetida. F. rubricaulis is 
claimed by Holmes to yield some of the white 
asafetida of commerce. Its mericarp fruits are 
said to be glabrous with broad thick wings, no 
vittae, the three, primary, dorsal ridges being in- 
conspicuous; there are 12 to 14 vittae on the 
dorsal and 8 to 10 on the ventral side, the cuticle 
on the dorsal surface is especially thick; the sub- 
epidermal tissue is many layers thick; the cells 
between the epidermis and the vittae are thin 
walled, while those on the opposite side of the 
vittae are tracheid-like in form. The plant is a 
native of Persia. 

On the basis of the study of fruits found in a 
mixed sample of gum resin of asafetida, J. Small 
concluded that Ferula rubricaulis yields some of 
the "white asafetida" and F. fcetida, the "red 
asafetida." Both of these varieties occur in com- 
merce. Both contain tears which when fresh are 
milky white or yellowish internally. In the case 
of the red variety, the freshly exposed surface of 
the fractured tear gradually changes in color to 
pink, red, and finally reddish-brown, whereas in 
that of the white variety it remains almost white. 

It is possible that asafetida is obtained from 
other species of Ferula, but the bulk of the drug 
probably comes from the plants named in the 
official definition. Among the other plants yielding 
asafetida is Ferula Narthex Boiss. While this is 
disputed by Aitchison yet it appears that it is 
the source of the gum-resin obtained from certain 
portions of Afghanistan. Tschirch describes this 
plant with illustrations in Schweiz Wchnschr. 
Pharm., 1910, p. 289. Holmes's discussion of the 
asafetida plants {Pharm. J., ser. iii, 19, 1888- 
1889) still remains one of our chief sources of 
information on the subject. (See also article on 
the sources of the fetid gum-resins by James 
Small, Pharm. J., 1913, 90, 287.) 

The asafetida plants are indigenous to western 
Afghanistan and eastern Persia. The great cab- 
bage-like heads of the asafetida plant, represent- 
ing the primary stage of the flower heads covered 



114 



Asafetida 



Part I 



over by the stipules of its leaves, are eaten raw 
by the natives as a sort of green. Collection of 
the drug begins in mid-April and proceeds until 
late in July. The root-stock is first laid bare by 
sawing off the head, those plants only which have 
not reached their flower-bearing stage being 
selected. A slice is then taken from the top of 
the root-stock, which is immediately covered with 
twigs and clay, forming a sort of dome, with an 
opening toward the north, so that the sun cannot 
get at the exposed root. About five or six weeks 
later, a thick, gummy, not milky, reddish sub- 
stance found upon the exposed surface of the rhi- 
zome in more or less irregular lumps is scraped 
off with a piece of iron hoop or removed with a 
slice of the rhizome and at once placed in a 
leather bag. The product of many plants is mixed 
and permitted to harden in the sun. The process 
is continued for a second and third time, the root- 
stock being cut lower on each occasion. 

Most of the drug is' normally gathered in eastern 
Persia and western Afghanistan. It is brought to 
Herat and Kandahar, whence it enters com- 
merce, being exported from Bunder Abbas and 
other Persian Gulf ports to Bombay and thence 
to Europe and the United States, usually arriving 
in tin-fined cases. In 1952 importations of the 
drug, from Iran, amounted to 83,175 pounds and 
from Switzerland, 11,200 pounds. 

Description. — "Asafetida occurs as a soft 
mass sometimes almost semi-liquid, or as irregu- 
lar, more or less pliable masses composed of 
agglutinated tears imbedded in a weak brown to 
moderate yellowish brown matrix, or as loose 
ovoid tears, from 0.5 to 4 cm. in diameter, with a 
few vegetable fragments. It becomes hard and 
occasionally brittle on drying. The surface of the 
freshly fractured tears is white to moderate yel- 
lowish brown, changing gradually on exposure 
to air or light to a strong pink and finally to a 
moderate yellowish brown. When moistened with 
water the tears become moderate orange to weak 
yellow. The odor is persistent and alliaceous, and 
the taste is bitter, alliaceous, and acrid." 7V..F. 

Standards and Tests. — Identification. — (1) 
A yellowish orange emulsion, turning to greenish- 
yellow on addition of alkalies, is formed when 
asafetida is triturated with water. (2) A reddish 
brown solution results when a fragment of asa- 
fetida is heated with sulfuric acid; on diluting 
this solution with a large volume of water, filter- 
ing, and alkalinizing the filtrate, a purplish blue 
fluorescence is produced. (3) A pink color is pro- 
duced on adding a few drops each of phloro- 
glucinol T.S. and hydrochloric acid to 10 ml. of 
the alcoholic extract obtained in the assay. Most 
foreign resins. — A yellowish brown color produced 
on adding a few drops of ferric chloride T.S. to 5 
ml. of the alcoholic extract obtained in the assay 
indicates absence of most foreign resins. Gal- 
banum. — A bluish green color, fading on stand- 
ing, obtained when enough hydrochloric acid to 
produce a faint turbidity is added to 10 ml. of 
alcoholic extract from the assay indicates absence 
of galbanum. Ammoniac. — No momentary yel- 
lowish orange to red color develops on adding 5 
ml. of sodium hypobromite T.S. to 2 ml. of a 1 in 
"24 aqueous emulsion of asafetida diluted with 5 



ml. of water. Rosin. — No green color is formed 
in the benzin layer on adding 10 ml. of a fresh 1 
in 200 solution of copper acetate to the filtrate 
from a 1 in 10 purified petroleum benzin extract 
of asafetida. Acid-insoluble ash. — Not over 15 
per cent. Alcohol-soluble extractive. — A sample 
of 2 Gm. of asafetida is extracted with alcohol in 
a Soxhlet or other extractor; the insoluble residue 
is dried at 105° for 2 hours and weighed. A cor- 
rection is applied for the amount of moisture in 
the drug, as determined by the toluene distillation 
method, and the content of alcohol-soluble extrac- 
tive calculated. Asafetida yields not less than 50 
per cent of such extractive. N.F. 

Constituents. — The odor of asafetida, and 
probably also its therapeutic virtues, depend 
chiefly upon its volatile oil. When freshly distilled 
it is a colorless liquid but it yellows on aging; it 
has an offensive odor and a taste which is at first 
flat but afterward bitter and acrid. According to 
Mannich and Fresenius {Arch. Pharm., 1936, 274, 
461), the main fraction of this oil is a mercaptan 
of the formula C7H14S2. Baumann (Quart. J. P., 
1929, 2, 621) found in a sample of asafetida 69 
per cent of an acetone-soluble resin fraction and 
31 per cent of gum and impurities. Of the resin 
fraction, 50.1 per cent (calculated to the original 
material) consisted of resin and ethereal oil. 1 per 
cent of ether-insoluble matter (apparently free 
resinol), 16.57 per cent of asaresinol ferulic acid 
ester and 1.33 per cent of free ferulic acid. The 
ester, which is very labile, is responsible for the 
change of color of asafetida on standing. The 
resinol is apparently a phenol and not coniferyl 
alcohol, as has been stated. Vanillin does not occur 
in the freshly gathered drug but is formed later 
by oxidation of the ferulic acid. On distillation of 
the resin in vacuo, umbelliferone was produced. 
Clevenger gives certain chemical and physical 
data on asafetida and its volatile oil, based upon 
examination of 41 lots of the drug offered for 
entry at the Port of New York (/. A. Ph. A., 
1932, 21, 668). The content of alcohol-soluble 
extractive varied from 54.5 to 74.7 per cent; that 
of volatile oil ranged between 7.5 and 12 ml. per 
100 grams of asafetida. 

Impurities and Adulterations. — Asafetida 
is often purposely adulterated; it frequently 
comes of inferior quality, and mixed with various 
impurities, such as sand, stones, galbanum, am- 
moniac, gums, gypsum, vegetable tissues, or a 
rose-colored marble. It is generally conceded to 
be the worst adulterated drug upon the market. 
The gum-resin imported from the Persian Gulf 
and Bombay is largely adulterated with sand and 
other gum-resins. In recent years, however, the 
quality of the available asafetida has materially 
improved. 

Asafetida is sometimes kept in a powdered 
state, but this is objectionable, as the drug loses 
volatile oil, and is more liable to adulteration. 
Powdered asafetida is best prepared by drying the 
crude drug over freshly burnt lime and then 
comminuting it at a low temperature. 

For methods which have been proposed for the 
detection of adulteration in asafetida, see U.S.D., 
22nd ed., p. 198. 

Uses. — Asafetida is seldom prescribed in the 



Part I 



Ascorbic Acid 



115 



United States. It appears to have been used in 
the East from the earliest times. Its therapeutic 
action probably arose from the psychic effect of 
its disagreeable odor and taste. In small amounts 
it gives the distinctive aroma to the type of sauce 
known as "Worcestershire." It is absorbed from 
the intestinal tract but there is no evidence that 
it has any distinct action. Pidoux took half an 
ounce at one dose without effects other than local 
action. 

Asafetida has been employed as a carminative 
in the treatment of flatulent colic. In colic, espe- 
cially in infants, it is often administered per 
rectum, either as the emulsion or as a suppository. 
The emulsion is prepared by triturating 4 Gm. of 
asafetida with 100 ml. of distilled water until a 
uniform mixture results, after which it is strained; 
15 to 30 ml. of this emulsion in 500 ml. of warm 
water may be given as an enema. Such an enema 
has been used for abdominal distention in pneu- 
monia and in postoperative cases; it is less irritant 
than the milk and molasses or the turpentine 
enema. Generally such enemas should not be given 
during the first 3 days after abdominal surgery, 
and the enema can should not be placed higher 
than 25 to 50 cm. above the level of the patient. 

Following absorption, the volatile oil of asa- 
fetida is eliminated through the lungs, for which 
reason the drug has been used as a stimulating 
expectorant in bronchitis, whooping cough, and 
asthma. 

Because of its disagreeable taste asafetida is 
preferably administered as a pill or coated tablet. 

Dose, 0.3 to 1 Gm. (approximately 5 to 15 
grains) . 



ASCORBIC ACID. U.S.P., B.P., LP. 

Vitamin C, [Acidum Ascorbicum] 



ASAFETIDA PILLS. 

[Pilulae Asafcetidae] 



N.F. 



Prepare 100 pills, according to the General Di- 
rections (see under Pills), from 20 Gm. of asa- 
fetida, and 6 Gm. of hard soap, in fine powder, 
using water as the excipient. Coat the pills, pref- 
erably with gelatin, or dispense the mass in gela- 
tin capsules. 

These pills are a convenient form for admin- 
istering asafetida, the unpleasant odor and taste of 
which render it very offensive, particularly when 
in liquid dispersion. 

Dose, one to three pills. 

ASAFETIDA TINCTURE. N.F. 

[Tinctura Asafcetidae] 

Tinctura Asa; Foetidae. Fr. Teinture d'asa foetida. Ger. 
Asanttinktur. It. Tintura di assa fetida. Sp. Tintirra de 
asafetida. 

Prepare the tincture, by Process M (see under 
Tinctures), from 200 Gm. of comminuted asa- 
fetida, using as the menstruum sufficient alcohol 
to make 1000 ml. of tincture. N.F. 

Alcohol Content. — From 78 to 85 per cent, 
by volume, of C2H5OH. N.F. 

Dose, 1 to 4 ml. (approximately 15 to 60 
minims). 

Storage. — Preserve "in tight, light-resistant 
containers and avoid exposure to direct sunlight 
or to excessive heat." N.F. 




"Ascorbic Acid, dried in a vacuum desiccator 
over sulfuric acid for 3 hours, contains not less 
than 99 per cent of CeHsOc." U.S.P. The B.P. 
defines ascorbic acid as the enolic form of 3-keto- 
L-gulofuranolactone; not less than 98 per cent of 
CeHsOe is required. The LP. requires not less 
than 98.0 per cent of CeHsOe, calculated with 
reference to the substance dried over sulfuric acid 
for 24 hours. 

Cevitamic Acid; Anti-scorbutic Vitamin. Ascorbin (.Lake- 
side); Cantaxin (Winthrop); Cebione (Merck) ; Cevalin 
(Lilly) ; Cevatine (Premo) ; Cevimin (Irwin, Neisler) ; 
Ciamin (Massengill) ; Vitacee (Endo). Sp. Acido Ascorbico. 

Scurvy has been for many centuries one of the 
great human plagues. It is said that in the 17th 
century more seamen died of scurvy than all other 
causes combined — and it has also been known for 
centuries that the disease was the result of dietetic 
deficiencies and could be cured with fresh green 
foods, lemon juice, and various other substances. 

In 1932, Waugh and King separated from 
lemon juice a "hexuronic acid" which possessed 
strong antiscorbutic properties. The announce- 
ment of this finding was followed in a few weeks 
by the report of Svirbely and Szent-Gyorgyi that 
"hexuronic acid" as prepared from adrenal glands 
was protective against scurvy. Within a short 
period of time several workers independently con- 
firmed the chemical identity of the vitamin and 
in 1933 its structural formula, as a lactone of 
hexuronic acid, was firmly established. Ascorbic 
acid occurs naturally in many plants, particularly 
in the fruits. Asenjo and Guzman {Science, 1946, 
103, 219) have reported that the West Indian 
cherry, which grows on small trees native to 
tropical and subtropical America, yields, on the 
average, 1.707 Gm. of ascorbic acid per 100 Gm. 
of cherries — approximately 34 times as much as 
from oranges. 

Even before the chemical structure was posi- 
tively known, methods for the synthesis of ascor- 
bic acid had been worked out. Because of the 
relationship of the acid to many known sugars 
and their derivatives, various syntheses of the 
former utilize the latter as starting compounds. 
The first synthesis of ascorbic acid used the rare 
sugar L-xylose. A later synthesis starts with 
D-glucose; this is first converted to the alcohol 
D-sorbital by catalytic hydrogenation, then oxi- 
dized through the action of Acetobacter sub- 
oxydans to L-sorbose (which has the same con- 
figuration at the fifth carbon atom as has ascorbic 
acid), following which the primary alcohol group 
in the Ci position of L-sorbose is oxidized to a 
carboxyl group. This step is rendered difficult 
because the L-sorbose molecule contains another 
primary alcohol group at the Ce position; this 
latter group must be protected against oxidation 
by converting the sugar to a diacetone derivative. 



116 



Ascorbic Acid 



Part I 



Following the oxidation (with potassium perman- 
ganate), the diacetone derivative is hydrolyzed to 
2-keto-L-gulonic acid and finally subjected to 
enolization and formation of the lactone ring to 
produce ascorbic acid. 

A number of sugar derivatives having struc- 
tures analogous to that of ascorbic acid, as well 
as stereoisomers of the latter, exhibit antiscor- 
butic action, but in no case does the activity ap- 
proach that of ascorbic acid. It appears certain 
that antiscorbutic activity is contingent on hav- 
ing the D-configuration of the fourth carbon atom 
in the molecule and the L-configuration of the 
fifth carbon atom. 

Description. — "Ascorbic Acid occurs as white 
or slightly yellow crystals or powder. It is odor- 
less, and on exposure to light it gradually darkens. 
In the dry state, Ascorbic Acid is reasonably 
stable in the air, but in aqueous solution it rapidly 
deteriorates in the presence of air. It melts at 
about 190°. One Gm.' of Ascorbic Acid dissolves 
in about 3 ml. of water and in about 30 ml. of 
aicohol; it is insoluble in chloroform, in ether, 
and in benzene." U.S.P. The B.P. gives the melt- 
ing point as between 190° and 192°, with decom- 
position; the I. P. requires it to be between 191° 
and 194°, with decomposition. 

Standards in Tests. — Optical rotation. — The 
specific rotation of ascorbic acid, determined with 
a 10 per cent w/v solution, is between +20.5° 
and +21.5°. Identification. — (1) Alkaline cupric 
tartrate T.S. is slowly reduced by a 1 in 50 solu- 
tion of ascorbic acid at room temperature, more 
readily when heated. (2) A blue color is immedi- 
ately produced on adding a few drops of sodium 
nitroprusside T.S. and 1 ml. of 0.1 N sodium 
hydroxide to 2 ml. of a 1 in 50 solution of ascorbic 
acid. (3) A blue color develops on heating with 
a drop of pyrrole 5 ml. of filtrate obtained from 
a well-shaken mixture of 15 mg. of ascorbic acid, 
dissolved in 15 ml. of a 1 in 20 solution of tri- 
chloroacetic acid, with 200 mg. of activated char- 
coal. Residue on ignition. — Not over 0.1 per cent. 
Heavy metals. — The limit is 20 parts per million. 
U.S.P. 

The B.P. requires an aqueous solution of ascor- 
bic acid to decolorize a solution of 2:6-dichloro- 
phenolindophenol. The specific rotation of a 2 
per cent w/v solution is stipulated as follows: 
22° to 23° in water; 50° to 51° in methyl alcohol. 
The I. P. specifices an ultraviolet absorbancy of 
550 in a 0.002 per cent w/v aqueous solution of 
pH 3, or less, at 245 mix. 

Preparation of Solutions of Ascorbic 
Acid. — It has long been known that prolonged 
boiling would destroy the antiscorbutic value of 
fresh foods, and it was at one time believed that 
this vitamin was heat-labile, but it is now known 
that the destruction of the vitamin is an oxidative 
process; ascorbic acid can be heated for long 
periods of time without change, provided all 
contact with oxygen is excluded. The products of 
oxidation of ascorbic acid in aqueous solution 
depend in part on the pH of the solution; in acid 
solutions the main product is dehydroascorbic acid 
while in alkaline solution hydrogen peroxide, oxa- 
.late ion and L-threonate ion are formed. (J.A.C.S., 



1943, 65, 1212). It is reported that solutions 
containing 10 per cent or more of ascorbic acid 
sometimes undergo a decomposition in which 
carbon dioxide is produced, and in such amount 
that dangerously high pressure may result in 
ampuls during normal storage. Unless oxygen is 
kept out of contact with aqueous solutions of 
ascorbic acid, or an antioxidant is used, the vita- 
min cannot be expected to remain stable. Pien 
and Meinrath (Compt. rend. acad. sc, 1939, 209, 
462) found that displacement of oxygen by carbon 
dioxide or nitrogen in aqueous solutions of as- 
corbic acid results in their retaining nearly 90 per 
cent activity after 20 minutes heating in an auto- 
clave. Some decomposition occurs also in the 
absence of oxygen, especially so if the solution 
is alkaline. U. S. Patent 2,297,212 discloses that 
the addition of thiourea (or its methyl or ethyl 
derivative) in concentrations of 0.005 per cent is 
effective in stabilizing ascorbic acid solutions ; the 
thiourea is harmless. The stabilizing effect of 
sodium chloride has also been reported, Vonesch 
and Remezzano (Chem. Abs., 1942, 36, 217) 
stating that addition of 3 parts of sodium chloride 
for each 10 parts of ascorbic acid sufficed to retard 
oxidation materially. Non-aqueous solvents, such 
as propylene glycol, are sometimes used with 
water in preparing injectable solutions of ascorbic 
acid. For data on the stability of ascorbic acid in 
various liquid formulations see Bandelin and 
Tuschhoff (/. A. Ph. A., 1955. 44, 241). 

Aqueous solutions of ascorbic acid, more prop- 
erly referred to as solutions of sodium ascorbate, 
may be prepared by the interaction of stoichio- 
metric quantities of ascorbic acid and sodium 
bicarbonate, while carbon dioxide is being passed 
through the solution; the pH of the solution 
should be adjusted to within 6.8 to 7.0 by the 
addition of ascorbic acid or sodium bicarbonate, 
as required. When required, a mixture of 0.09 per 
cent of methylparaben and 0.01 per cent of 
propylparaben may be used as bacteriostatic 
agents. Ampuls may be sterilized at 120° for 15 
minutes. Ciminera and Wilcox (/. A. Ph. A., 
1946, 35, 363) found that a solution of ascorbic 
acid, adjusted to a pH of 6.0 to 6.5 with trisodium 
phosphate and protected from air during manipu- 
lation, was stable for at least one year at room 
temperature in the dark. 

Assay. — The U.S. P. directs that about 400 mg. 
of ascorbic acid, previously dried in a vacuum 
desiccator over sulfuric acid for 3 hours, be 
titrated with 0.1 A 7 iodine in an acid solution; 
each molecule of ascorbic acid reacts with a mole- 
cule of iodine to form dehydroascorbic acid and 
two iodide ions. Each ml. of 0.1 N iodine repre- 
sents 8.806 mg. of CeHgOe. U.S.P. Bandaruk 
(Am. J. Pharm., 1941, 113, 18) and later Goett 
et al. (J. A. Ph. A., 1943, 31, 7) advocated titra- 
tion with potassium iodate solution as giving a 
more satisfactory end-point than obtained with 
iodine solution. 

The B.P. assay utilizes the same reaction as 
employed in the U.S.P. except that the former 
directs titration of a 40-mg. sample with 0.01 N 
iodine solution. The LP. assay employs about 
900 mg. of ascorbic acid, neutralizes it with 0.1 N 



Part I 



Ascorbic Acid 



117 



sodium hydroxide in the presence of phenol- 
phthalein, adds 50 ml. of 0.1 N iodine and titrates 
the excess iodine with 0.1 N sodium thiosulfate. 

The facility with which ascorbic acid is oxidized 
to dehydroascorbic acid is the basis of several 
other chemical assay procedures. Besides iodine, 
ascorbic acid will reduce ferricyanides, copper 
sulfate, methylene blue, etc. Perhaps the most 
important method of determining ascorbic acid 
in natural products is that involving decoloriza- 
tion of the dye dichlorophenolindophenol. For a 
description of this assay, which is also applied to 
the official tablets, see Bessey, J.A.M.A., 1938, 
111, 1291. Schmall et al. {Anal. Chem., 1954, 26, 
1521) recently described a new method for the 
colorimetric determination of ascorbic acid, this 
depending on its interaction with diazotized 4- 
methoxy-2-nitroaniline, the product having a 
stable blue color in alkaline solution. 

Uses. — Scurvy. — The disease known as scurvy, 
for centuries one of the major plagues of human- 
ity, especially in areas where the populace has 
been unable to obtain fresh fruit or vegetables, 
is caused by a lack of ascorbic acid. Frank scurvy 
is less frequent now than formerly; in the United 
States it is seen in infants (Follis et al., Bull. 
Johns Hopkins Hosp., 1950, 87, 569) and in 
indigent old men living alone. Most lower forms 
of animals appear to be able to synthesize ascorbic 
acid, but guinea pigs and primates must ingest 
this essential substance in their food supply. The 
amount of ascorbic acid in a diet of cow's milk 
(about 0.7 mg. per 100 ml. of milk) is insufficient 
for either an infant or an adult with peptic ulcer; 
milk from a well-nourished woman contains the 
adequate amount of approximately 5.2 mg. per 
100 ml. 

The outstanding symptoms of scurvy are great 
fragility of the blood capillaries (Hines and 
Parker, Quart. Bull. Northwest U. Med. Sch., 
1949, 23, 424), as shown by a tendency to ex- 
ternal or internal hemorrhage on the slightest 
injury, improper development of the teeth or 
periodontal hemorrhage and inflammation after 
eruption of teeth, and great muscular weakness. 
The underlying pathology is a change in the char- 
acter of the intercellular matrix of the connective 
tissues (Dalldorf, J. A.M. A., 1938, 111, 1376). 
Fibroblasts and ground substance are formed, but 
collagen, osteoid tissue and dentine fail to form 
(Follis, Bull. Johns Hopkins Hosp., 1951, 89, 9). 
Severe deficiency of ascorbic acid may occur in 
surgical conditions and result in disruption of 
wounds {New Eng. J. Med., 1942, 226, 469; Am. 
J. Surg., 1944, 66, 220), and failure of union of 
fractures {Proc. Roy. Soc. Med., 1944, 37, 275). 
Scorbutic patients often show evidence of de- 
generation of skeletal muscles, anemia, enlarge- 
ment of the heart, atrophy of the adrenals, 
lowered resistance to infection, and disturbances 
of calcium metabolism. Roentgen examination 
often shows subperiosteal hemorrhages, broad 
epiphyses and interruptions in the lamina dura of 
the teeth. Physicians always look for swollen, 
spongy, interdental papillae, of a blue or brown- 
red color, which bleed easily, as a sign of scurvy, 
although McMillan and Inglis {Brit. Med. J., 



1944, 2, 233) reported gingivitis in only 8 of 53 
cases of scurvy. 

A megaloblastic anemia in infants was described 
by Zuelzer and Ogden {Am. J. Dis. Child., 1946, 
71, 211) which responded to treatment with folic 
acid but not to iron or the vitamin B12 in liver 
extract. Analysis of the reported cases, and feed- 
ing experiments on monkeys, demonstrated that 
vitamin C deficiency in the diet of the infant was 
responsible for the megaloblastic type of anemia 
(May et al, ibid., 1950, 80, 191; 1952, 82, 282). 
Treatment with ascorbic acid corrected the me- 
galoblastic bone marrow and the anemia slowly. 
If vitamin B12 was injected intramuscularly, cor- 
rection was as rapid as with administration of 
folic acid by mouth. 

Physiological Function. — The physiological 
role of ascorbic acid is beginning to unfold. 
Sealock and Goodland {Science, 1951, 114, 645) 
reported that ascorbic acid is an essential co- 
enyme in the metabolic oxidation of tyrosine and 
phenylalanine. Scorbutic guinea pigs and humans 
excrete homogentisic acid and other hydroxy- 
phenyl compounds in the urine; oxidation of the 
phenyl nucleus seems to require ascorbic acid 
(Rogers and Gardner, /. Lab. Clin. Med., 1949, 
34, 1491). Urinary excretion of p-hydroxyphenyl- 
pyruvic acid and />-hydroxyphenyllactic acid in 
premature infants is corrected by administration 
of ascorbic acid. Histochemical studies of experi- 
mental wound healing in guinea pigs receiving 
vitamin C demonstrate the presence of an acid 
mucopolysaccharide in the early days of healing 
which is shown by incubation with hyaluronidase 
to be hyaluronic acid or chondroitin sulfate; this 
ground substance is not found in wounds of 
scorbutic animals (Penney and Balfour, /. Path. 
Bad., 1949, 61, 171). An abnormal mucopoly- 
saccharide and an abnormal precollagen have been 
found in such wounds (Bradfield and Kodicek, 
Biochem. J., 1951, 49, xvii). Even six weeks after 
receiving an experimental wound well-nourished 
guinea pigs, with good gross and microscopic evi- 
dence of fibrotic healing, when fed for 18 days 
on a vitamin C-deficient diet developed swelling, 
herniation and hemorrhage in the scars, with his- 
tologic evidence of degenerative changes, although 
the overlying epithelium and the adjacent con- 
nective tissue appeared normal (Pirani and Leven- 
son, Proc. S. Exp. Biol. Med., 1953, 82, 95). Even 
maintenance of a recent scar seems to require 
adequate amounts of vitamin C. An increase in 
the blood serum concentration of glycoproteins 
was observed in scorbutic guinea pigs by Pirani 
{Arch. Path., 1951, 51, 597); administration of 
ascorbic acid is followed by a return to a normal 
concentration. It is suggested that ascorbic acid 
deficiency results in a depolymerization of carbo- 
hydrate-containing constituents of the ground 
substance of connective tissue, with absorption of 
the smaller molecule into the blood stream. Rep- 
pert et al. {Proc. S. Exp. Biol. Med., 1951, 77, 
318) believe that ascorbic acid may inhibit the 
hyaluronidase-hyaluronic acid system in inter- 
stitial substance; loss of support for the capil- 
laries from the surrounding ground substance 
would be expected to increase capillary fragility. 



118 



Ascorbic Acid 



Part I 



Daubenmerkl (Acta Pharmacol. Toxicol., 1951, 
7, 153) observed that ascorbic acid, in minute 
concentrations in vitro, decreased the viscosity of 
hyaluronic acid solutions at pH 7; with higher 
concentrations of ascorbic acid this depolymeriz- 
ing action was augmented and accelerated by the 
addition of hydrogen peroxide and such a mixture 
was an effective "spreading factor" for adminis- 
tration of fluids by hypodermoclysis in children. 
For clinical purposes this spreading factor is less 
desirable than hyaluronidase because of some 
irritation and the necessity for regulating the dose 
within narrow limits. 

In line with the observations of Moon and 
Rhinehart (Circulation, 1952, 6, 481), Duff (Arch. 
Path., 1935, 20, 371) and Aschoff, that the initial 
lesion in atherosclerosis is an alteration in the 
intercellular ground substance of the artery, 
Willis (Can. Med. Assoc. J., 1953, 69, 17) re- 
ported some thought-provoking observations. 
Atherosclerosis was found in guinea pigs with 
acute or chronic scurvy and with normal blood 
cnolesterol levels and without lipid deposits in 
the reticuloendothelial system; this simulates 
human atherosclerosis more than does the ex- 
perimental cholesterosis in rabbits or chickens fed 
large amounts of fat and cholesterol. 

Adrenals, Stress and Ascorbic Acid. — The 
rapid depletion of ascorbic acid in almost any 
severe illness has long been recognized. For ex- 
ample, the concentration in blood and urine 
drops rapidly to low levels in severe burns 
(Levenson et al., Ann. Surg., 1946, 124, 840). 
Furthermore, a large dose of ascorbic acid in such 
a patient is not excreted but is retained in the 
body, to be destroyed or utilized. The high con- 
centration of ascorbic acid in the adrenal gland, 
along with its rapid increase (as well as of cho- 
lesterol) following administration of corticotropin 
or application of stress, have resulted in con- 
siderable study of the relationship of adrenal 
corticoids and ascorbic acid (Sayers, Physiol. 
Rev., 1950, 30, 241). The mechanism of this 
relation is apparently not to be found in the 
adrenal gland since no evidence of deficiency in 
adrenal corticoids can be found in scorbutic 
humans or animals (see Nutr. Rev., 1954, 12, 
81). In fact, blood and urine levels of 17-hydroxy- 
corticoids are increased in scurvy, and studies 
with carbon- 14-labeled acetate in animals showed 
greater conversion to adrenal cholesterol than in 
well-nourished animals which served as a control 
(Becker et al, J.A.C.S., 1953, 75, 2020). An in- 
creased urinary excretion of corticoids, but not 
of 17-ketosteroids, was found in children given 
both corticotropin and ascorbic acid (Sprechler 
and Vesterdal, Acta Endocrinol., 1953, 12, 207). 
In rats, salicylates cause a decrease in adrenal 
ascorbic acid, but not of cholesterol (Comulada 
et al., Fed. Proc, 1953, 12, 313). 

Metabolism. — Ascorbic acid is not stored in 
the body to any considerable extent. In the ex- 
periments of Crandon (New Eng. J. Med., 1940, 
223, 353), who lived on a diet completely lack- 
ing in ascorbic acid but adequate in all other sub- 
stances, the blood plasma ascorbic acid fell within 
.10 days to a low level and in 41 days completely 



to zero. However, the concentration of ascorbic 
acid in the leukocyte and platelet layer of the 
blood did not drop to zero until 130 days. Hyper- 
keratotic papules appeared on the thighs after 132 
days and perifolicular hemorrhage after 161 days. 
An incision in the skin healed normally after 95 
days on the diet, when the blood plasma level of 
ascorbic acid was, and had been, zero for 44 days, 
but the white cell-platelet layer contained 4 mg. 
of ascorbic acid per 100 Gm. After 160 days 
clinical scurvy was present and an incision did not 
heal until ascorbic acid was given. Pijoan and 
Lozner (Bull. Johns Hopkins Hosp., 1944, 75, 
303) confirmed Crandon's findings. 

A portion of the ascorbic acid ingested with the 
normal diet appears to be destroyed in the body 
but a greater part is excreted. The rate of excre- 
tion in the urine affords a criterion of the amount 
in the blood. The renal threshold is about 1.4 mg. 
per 100 ml. of plasma (Arch. Int. Med., 1945, 75, 
407). Ascorbic acid is excreted in sweat, but 
Henschel and his associates (Am. J. Trop. Med., 
1944, 24, 259) believe this to be negligible and 
found no evidence for an increased requirement 
for vitamin C in hot environments. Although 
Crandon and others have shown that less than 
25 mg. of ascorbic acid per 100 Gm. in the white 
cell-platelet layer of the blood is a better criterion 
of deficiency than a decrease in the blood plasma 
level, Kyhos, Sevringhaus and Hagedorn (Arch. 
Int. Med., 1945, 75, 407) reported that persons, 
sick or well, who regularly ingest adequate 
amounts of vitamin C-containing food seldom have 
fasting blood plasma values lower than 0.8 mg. 
per 100 ml. They do not believe that determina- 
tions of ascorbic acid in whole blood are superior 
to determinations in plasma. The disagreement 
continues. After depletion of normal adult humans 
with a daily intake of 10 mg. of ascorbic acid or 
less to three-fourths to one-half of the initial 
concentration in white blood cells, Steele et al. 
(Fed. Proc, 1953, 12, 430) found that a daily 
intake of 40 mg., but not of 20 or even 30 mg., 
caused an increase in the white blood cell content 
of ascorbic acid, with a persistently low plasma 
concentration of 0.2 mg. per 100 ml. Lutz et al. 
(ibid., 1954, 13, 466) reported that subjects 
saturated with ascorbic acid from a period of 
large daily intake failed to maintain their high 
concentration in the white blood cells on a daily 
intake of 40 mg.; depleted subjects, however, did 
maintain their initial subnormal concentration on 
this daily intake. The minimum normal blood 
plasma ascorbic acid concentration is 0.8 mg. per 
100 ml. In many persons the concentration is 
slightly lower in the spring of the year as a result 
of the lower intake of fresh fruits and vegetables 
during the winter period. 

Optimal Nutritional Requirement. — In nor- 
mal conditions the daily requirement for main- 
tenance of optimal health in the adult male is 
given as 75 mg. by the National Research Council 
(U.S.A.). The Canadian Council on Nutrition 
(Can. Pub. Health J., 1949, 40, 420), however, 
recommended 30 mg. daily as adequate. On the 
basis of the incidence of illness in a controlled 
population, Scheunert (Intern. Ztschr. Vitamin- 



Part I 



Ascorbic Acid 



119 



forsch., 1949, 20, 374) reported that 100 or even 
300 mg. is to be preferred. The recommended 
daily dietary allowances of the National Research 
Council (U.S.A.) are as follows: man (65 Kg.), 
75 mg.; woman (55 Kg.), 70 mg.; during preg- 
nancy (third trimester), 100 mg.; during lacta- 
tion, 150 mg.; infants, 30 mg.; children (1 to 
3 years old), 35 mg.; children (4 to 6 years old), 
50 mg.; children (7 to 9 years old), 60 mg.; chil- 
dren (10 to 12 years old), 75 mg.; girls from 13 
to 20 years old, 80 mg.; boys from 13 to 20 years 
old, 90 to 100 mg. 

These recommendations find confirmation in 
the report of Wilson and Lubschez (/. Clin. Inv., 
1946, 25, 428) that from 50 to 75 mg. was the 
amount required daily by normal children averag- 
ing seven years of age to maintain a level of 25 
mg. per cent of ascorbic acid in the white cell- 
platelet layer. They believe this level to be a 
better criterion of habitual intake of the vitamin 
than either plasma or urine levels. It is claimed 
that a very considerable proportion of the popula- 
tion is suffering from subclinical scurvy, that is, 
from a partial deficiency of ascorbic acid 
(J.A.M.A., 1942, 118, 944). From 1.4 to 1.8 mg. 
per Kg. of body weight was required daily by 
young women to produce saturation with the 
vitamin as evidenced by urinary excretion of 50 
per cent of a test dose of 400 mg. orally (Kline 
and Eheart, /. Nutrition, 1944, 28, 413). How- 
ever, both Crandon (loc. cit.) and Pijoan and 
Lozner (New Eng. J. Med., 1944, 231, 14) 
showed that saturation, as evidenced by overflow 
in the urine, is not essential for health; from 12 
to 25 mg. of ascorbic acid daily maintained a 
normal concentration in the white cell-platelet 
layer and permitted normal wound healing. Najjar 
et al. (Bull. Johns Hopkins Hosp., 1944, 75, 315) 
confirmed the adequacy of 18 to 25 mg. of ascor- 
bic acid daily for young adults. In 20-year-old 
male students in Iceland habitually on a diet of 
about 20 mg. ascorbic acid daily, Sigurjonsson 
(Brit. J. Nutrition, 1951, 5, 216) studied the 
urinary excretion when 10 mg. per Kg. per day 
was fed. A maximum output of 50 to 60 per cent 
of the dose was reached on the second or third 
day, decreasing thereafter despite continuation of 
the high intake; this suggests an increased rate 
of destruction. A diuretic effect has been reported 
in man following large doses (700 mg.) by mouth, 
but not intravenously; ascorbic acid has been 
used effectively in the treatment of edema 
(Shaffer, J. A.M. A., 1944, 124, 700). 

Therapeutic Uses. — Ascorbic acid is used as 
a specific curative in scurvy. In many different 
diseases a deficiency of the vitamin may develop 
due to anorexia, to fault of a special diet, to 
failure of absorption as in diarrheal and other 
disorders, or to increased requirements in hyper- 
metabolism (Proc. S. Exp. Biol. Med., 1938, 39, 
233; Bull. Johns Hopkins Hosp., 1938, 63, 31) 
or during the course of infections. The correction, 
or better the prevention, of any deficiency of 
ascorbic acid will benefit such patients. 

Detoxification. — Ascorbic acid has a detoxify- 
ing action toward many toxins, drugs and indus- 
trial chemicals (J. A.M. A., 1943, 121, 868; Arch. 



Int. Med., 1943, 71, 315). Thus, it is of value 
in connection with arsenicals, such as neoarsphen- 
amine (J. A.M. A., 1941, 117, 1692; Am. J. Digest. 
Dis., 1943, 10, 170; /. Pharmacol, 1944, 80, 
81), benzene and trinitrotoluene (J -Lancet, 1943, 
63, 349), bismuth and antimony compounds (Am. 
J. Digest. Dis., 1943, 10, 170), the sulfonamides 
(Arch. Int. Med., 1942, 69, 662), intravenous 
procaine hydrochloride (J.A.M.A., 1951, 147, 
1761); Arch. Dermat. Syph., 1952, 65, 39), 
salicylates (/. Lab. Clin. Med., 1942, 28, 28), 
diethylstilbestrol (J.A.M.A., 1943, 123, 113), 
gold salts (New Eng. J. Med., 1943, 229, 773; 
J.A.M.A., 1942, 120, 1331), and lead (/. Lab. 
Clin. Med., 1941, 26, 1478). However, the bene- 
ficial effect in lead poisoning has been denied 
(J. A.M. A., 1943, 121, 501). The hypnotic action 
of phenobarbital or pentobarbital is greater in 
scorbutic guinea pigs (/. A. Ph. A., 1941, 30, 
613); Greig (/. Pharmacol, 1947, 91, 317) de- 
scribed a depression of oxidative metabolism in 
the brain by barbiturates which was corrected, 
in vitro, with ascorbic acid. McCormick (Arch. 
Pediat., 1953, 70, 107) recommended use of 
ascorbic acid to minimize the alleged undesirable 
results to be expected from drinking public water 
supplies to which fluoride has been added in a 
"misguided" effort to prevent dental caries. Bour- 
quin and Musmanno (Am. J. Digest. Dis., 1953, 
20, 75) found that smoking of cigarettes or 
addition of nicotine to blood, in vitro, decreased 
the concentration of ascorbic acid in blood. In- 
travenous injection of 1 Gm. of sodium ascorbate 
at the time that a patient taking tetraethyl- 
thiuram disulfide is given ethyl alcohol relieved 
headache, restlessness, palpitation, weakness and 
apprehension but did not prevent the increase in 
acetaldehyde concentration in blood or the hypo- 
tension, tachycardia and flushing of the skin 
(Niblo et al, Dis. Nerv. System, 1951, 12, 340). 
Greiner and Gold (J. A.M. A., 1953, 152, 1130) 
did not find any decrease in the incidence of un- 
toward effects when ascorbic acid was added to 
meralluride administered by mouth as a diuretic. 
Treatment of Various Disorders. — Ascorbic 
acid, being related to the functioning of inter- 
cellular substance, has come into consideration in 
all phases of physiology and pathology and has 
been tried in the treatment of almost all of the 
disorders of mankind. Benefit has been reported 
in: retinal hemorrhage (Am. J. Obst. Gyn., 1943, 
46, 635), coronary thrombosis (Can. Med. 
Assoc. J., 1941, 44, 114), hematuria (/. Urol, 
1939, 41, 401), bleeding peptic ulcer (Ann. Int. 
Med., 1940, 14, 588), peptic ulcer without hem- 
orrhage (Am. Pract., 1952, 3, 117), rheumatic 
fever, diphtheria, pneumonia and scarlet fever 
(Am. J. Dis. Child., 1942, 64, 426), acute rheu- 
matic fever (New Eng. J. Med., 1950, 242, 614) 
(in doses of 1 Gm. by mouth 4 times daily), 
healing of deep but not of superficial corneal 
ulcers (Brit. M. J., 1950, 2, 1145), tuberculosis 
(Am. Rev. Tuberc, 1941, 44, 596), grippe 
(Laryn., 1938, 48, 327), dysentery (Clin. Proc, 
1943, 2, 65), fractures (Klin.-therap. Wchnschr., 
1937, 16, 1313), prickly heat rash on the skin 
(J.A.M.A., 1951, 145, 175), march hemoglobinuria 



120 



Ascorbic Acid 



Part I 



(Lancet, 1949, 1, 435), and dental caries (Ann. 
Int. Med., 1944, 20, 1). The relation of ascorbic 
acid to gastrointestinal disease seems to have sig- 
nificance. Freeman and Hafkesbring (Fed. Proc, 
1954, 13, 48) found that both blood and gastric 
juice ascorbic acid concentrations were about one- 
half that of healthy persons in patients with peptic 
ulcer, gastritis, pernicious anemia, and carcinoma 
of the stomach. The studies of Breidenbach and 
Roy (ibid., 1953, 12, 182) indicated that ascorbic 
acid retarded proteolysis in mixtures with crude 
gastric juice; in cases of peptic ulcer such an 
action would minimize the concentration of acid 
and pepsin acting on the gastric mucosa. 

The value of ascorbic acid in the following con- 
ditions, among others, is controversial: hay fever 
(Ann. Allergy, 1949, 7, 65), fatigue (J. -Lancet, 
1943, 63, 355), hot environment (Science, News 
Sup., June 19, 1942, p. 12; but see /. Allergy, 
1945, 16, 14), and bleeding gums and gingivitis 
(Am. J. Pharm., 1943, 115, 238; Lancet, 1943, 

I, 640; but see Am. J. Obst. Gyn., 1951, 61, 
1348; /. A. Dent. A., 1944, 31, 1323), in com- 
bination with menadione in hyperemesis gravi- 
darum (Am. J. Obst. Gyn., 1952, 64, 416), in 
combination with procaine hydrochloride orally 
in pruritus in allergic patients (Ann. Allergy, 1953. 

II, 85), in virus infections in children (measles, 
mumps, chicken pox, pneumonia, encephalitis and 
poliomyelitis) (South. Med. Surg., 1951, 113, 
101), and intravenously in combination with 
desoxycorticosterone glucoside for temporary re- 
lief in rheumatoid arthritis (Lancet, 1952, 1, 
1280). In a carefully controlled study of ascorbic 
acid and other vitamins, Cowan et al. (J.A.M.A., 
1942, 120, 1268) observed no benefit in the pre- 
vention of the common cold. The relationship 
between the blood plasma ascorbic acid level and 
the titer of complement (J. A.M. A., 1939, 112, 
1449) was not confirmed (/. Immunol., 1942, 44, 
289). The addition of ascorbic acid did not en- 
hance the effect of ferrous iron therapy in ele- 
vating the blood hemoglobin level of school chil- 
dren (Brit. M. J., 1944, 1, 76). Ruskin (Am. J. 
Digest Dis., 1945, 12, 281), in experiments on 
rabbit bronchiolar tissue, demonstrated ascorbic 
acid to have antihistaminic activity. (Y) 

Toxicology. — Untoward effects from either 
oral use or proper parenteral administration of 
appropriate solutions of ascorbic acid are almost 
unknown. Cases of acute hemolytic anemia in 
children ingesting a solution of ^-aminosalicylic 
acid containing sodium ascorbate have been re- 
ported (Lust, Scalpel, 1953, 106, 276; abstracted 
in J.A.M.A., 1953, 152, 1281). Lowry et al. (Proc. 
S. Exp. Biol. Med., 1952, 80, 361) fed four adult 
humans 1 Gm. of ascorbic acid daily, in three 
divided portions with meals, for three months 
without untoward symptoms, and with no altera- 
tion in the concentrations of the vitamin in blood 
or urine at the end of the period as compared 
with the first few weeks. 

Parenteral Administration. — When intes- 
tinal absorption of ascorbic acid is inefficient or 
when a massive effect is desired sodium ascorbate 
may be injected subcutaneously or intravenously 
. (see above for description of preparation of solu- 
tions of the salt). Because of the strong acidity of 



ascorbic acid, which has been observed to cause 
an increase in the blood pressure of animals, the 
acid itself should not be used in this manner. 
Under the name Cenolate (Abbott) a methyl 
glucamine salt is available for intravenous, sub- 
cutaneous or intramuscular injection. 

Antioxidant Action. — The instability of as- 
corbic acid in the presence of water is mainly 
attributable to the ease of its oxidation, as by air. 
Because of this, ascorbic acid may serve to pre- 
vent oxidation of other substances. Since ascorbic 
acid is available in large quantities, and is rela- 
tively inexpensive, it is sometimes used for this 
purpose. One ingenious application is the use of 
ascorbic acid to prevent change of flavor or dis- 
coloration of canned or frozen fruits, such as the 
peach; 150 mg. of the acid per pound of fruit is 
effective. Development of rancidity in butter, at 
37°, was found to be retarded by addition of 0.01 
per cent of L-ascorbyl stearate, palmitate, myris- 
tate or laurate (Mukherjee and Goswami, /. In- 
dian Chem. Soc, 1950, 27, 539; see also Watts 
and Wong, Arch. Biochem., 1951, 30, 110). 

Dose. — The usual therapeutic dose of ascorbic 
acid is 150 mg. (approximately 2 l / 2 grains) daily, 
by mouth, or by subcutaneous or intravenous ad- 
ministration of sodium ascorbate injection; the 
range of dose is 100 mg. to 1 Gm. The optimal 
daily requirement in health is 75 mg. for an adult, 
with a range of 25 to 75 mg.; for a child it is 
50 mg. daily. An infant receiving a formula of 
modified cow's milk should receive 5 mg. daily. 
In severe illness the recommendation of Pijoan 
and Lozner (New Eng. J. Med., 1944, 231, 14) 
to take 1 Gm. daily for ten days is worthwhile. 

The dose of ascorbic acid was formerly ex- 
pressed in terms of units. The U.S. P. XII defined 
its unit as follows: "One United States Phar- 
macopoeial Unit of Ascorbic Acid (Vitamin C) 
is the Vitamin C activity of 0.05 mg. of the U.S. P. 
Reference Standard, and is equal to one Interna- 
tional Unit of Vitamin C as defined and adopted 
by the Conference of Vitamin Standards of the 
Permanent Commission on Biological Standardiza- 
tion of the League of Nations in June of 1934." 
U.S.P. XII. 

Storage. — Preserve "in tight containers." 
U.S.P. 

Off. Prep. — Ascorbic Acid Tablets, U.S.P., 
B.P.; Decavitamin Capsules; Decavitamin Tab- 
lets, U.S.P.; Hexavitamin Capsules; Hexavitamin 
Tablets, N.F. 

ASCORBIC ACID INJECTION. U.S.P. 

Sodium Ascorbate Injection, U.S.P. XIV 

"Ascorbic Acid Injection is a sterile solution of 
ascorbic acid in water for injection prepared with 
the aid of sodium hydroxide, sodium carbonate, or 
sodium bicarbonate. It contains not less than 95 
per cent and not more than 115 per cent of the 
labeled amount of C6Hs06." U.S.P. 

For a discussion of methods of preparing this 
injection see the preceding monograph. The 
U.S.P. requires the pH of the injection to be be- 
tween 5.5 and 7.0. The assay utilizes the method 
described under Ascorbic Acid Tablets. 

Storage. — Preserve "in single-dose containers, 
preferably of Type I or Type II glass." U.S.P. 



Part I 



Aspidium 121 



Usual Sizes.— 100 and 500 mg. in 2 ml.; 500 
mg. and 1 Gm. in 5 ml.; 500 mg. in 10 ml. 

ASCORBIC ACID TABLETS. 

U.S.P. (B.P., I.P.) 

Tabellas Acidi Ascorbici 

"Ascorbic Acid Tablets contain not less than 
95 per cent and not more than 115 per cent of the 
labeled amount of CeHs06." U.S.P. The corre- 
sponding limits of the B.P. are 88.0 per cent and 
110.0 per cent; the I.P. limits are 90.0 and 110.0 
per cent, respectively. 

B.P. Tablets of Ascorbic Acid. I.P. Compressi Acidi 
Ascorbici. Sp. Tabletas de Acido Ascorbico. 

Assay. — Because the tablets will in all likeli- 
hood contain other substances, besides ascorbic 
acid, which reduce iodine it is not possible to de- 
termine the content of ascorbic acid in the tablets 
in the same manner as the pure acid is analyzed. 
By using dichlorophenol-indophenol solution, how- 
ever, the ascorbic acid may be oxidized — to dehy- 
droascorbic acid, the same product as obtained in 
the titration with iodine — without oxidizing any 
other constituent that may normally be in the 
tablet. Dichlorophenol-indophenol is blue in alka- 
line solution, pink in acid and colorless when it is 
reduced. For this titration the reagent is used in 
alkaline solution; on addition to the ascorbic acid 
solution it is decolorized and the end point is 
taken to be the appearance of a rose-pink color in 
the solution which persists for at least 5 seconds. 
The formation of the pink color is due to the fact 
that the titration medium contains acid, which 
changes the blue color of the titrating solution 
to pink. The dichlorophenol-indophenol solution 
is standardized against pure ascorbic acid. U.S.P. 

Ascorbic acid tablets are frequently yellowish 
in color but this should not be interpreted as 
necessarily indicating extensive decomposition. 
Such discolored tablets may readily meet the offi- 
cial assay requirement. 

Under the name Sodascorbate (Van Patten) 
there is available sodium ascorbate, in tablets, for 
use in all conditions for which ascorbic acid is 
given orally. The sodium salt has the advantage 
of minimizing disturbance which may be caused 
by the acidity of ascorbic acid, especially when 
large doses of the latter are given. 

Usual Sizes.— 25, 50, 100, 250 and 500 mg. 

ASPIDIUM. U.S.P. (B.P, I.P.) 

Male Fern, [Aspidium] 

"Aspidium consists of the rhizome and stipes 
of Dryopteris Filix-mas (Linne) Schott, known in 
commerce as European Aspidium or Male Fern, 
or of Dryopteris marginalis (Linne) Asa Gray, 
known in commerce as American Aspidium or 
Marginal Fern (Fam. Polypodiacece) . Aspidium 
yields not less than 1.5 per cent of crude filicin." 
U.S.P. 

The B.P. recognizes Male Fern as the rhizome, 
frond-bases and apical bud of Dryopteris filix-mas 
(L.) Schott, collected late in the autumn, divested 
of roots and dead portions and carefully dried, 
retaining the internal green color; not less than 
1.50 per cent of filicin is required. The I.P. defi- 



nition and requirement of filicin content are prac- 
tically the same as those of the B.P. except that 
Dryopteris marginalis is also recognized as a 
source of the drug. 

B.P., I.P. Male Fern; Filix Mas. European Aspidium; 
Basket Fern. Rhizoma Filicis; Filicis Maris Rhizoma. Fr. 
Fougere male. Ger. Farnwurzel ; Johanniswurzel. It. Felce 
maschio. Sp. Rizoma de helecho macho; Aspidio. 

Since the term Dryopteris was first used by 
Amman in 1739, and applied in 1763 by Adam- 
son, as the name of the genus to which the 
Aspidium was applied in 1800 by Swartz, the use 
of the generic term Dryopteris is necessitated by 
the rules of botanic nomenclature. The synonyms 
for the male fern are extraordinarily numerous. 
The following have been among those occasionally 
used: Aspidium Filix-mas, of many authors; 
Polypodium Filix-mas Linn.; and Polystichum 
Filix-mas Roth. 

The Male Fern is very widely distributed, oc- 
curring in Greenland, Europe, Asia, Northern 
Africa and in some of the Polynesian Islands; 
in the Western Hemisphere it is found in the 
Rocky Mountains in North America and the 
Andes Mountains in South America. It has a 
perennial, oblique rhizome, from which numerous 
annual fronds arise, forming tufts from a foot 
to four feet in height. The stipe, or petiole, and 
midrib are thickly beset with brown, tough, trans- 
parent scales; the frond itself is ovate-oblong in 
outline, the pinnae being linear-lanceolate, taper- 
ing from base to apex. The fructification is in 
small dots on the back of each lobe, occurring 
close to the midvein. 

The leather wood jern or marginal fern, Dry- 
opteris marginalis (L.) Asa Gray (Aspidium 
marginale Sw. ; Polypodium marginale L.), differs 
from the preceding by having the sori (fruit 
bodies) on the margin of the leaves instead of 
near the midrib. It is found in rocky woods and 
on banks in eastern North America from Nova 
Scotia to Alabama. Wilson (Thesis, Massachusetts 
Coll. Pharm., 1925) found the oleoresin from the 
marginal fern to yield from 22 to 24 per cent of 
crude filicin. 

It is probable that all of the species of this 
genus possess more or less anthelmintic prop- 
erties. According to Rosendahl (Pharm. J., 1911, 
87, 35) the Dryopteris dilatata is indeed four 
times as active a poison to the tapeworm as the 
true aspidium. D. spinulosa Kuntze is often found 
mixed with the male fern in Germany. Lauren 
(Apoth.-Ztg., 1903) stated that this species is an 
active taeniacide less liable to cause disagreeable 
sensations. The D. rigida Underw. of the Pacific 
coast is used in the western U. S. as a vermifuge. 

The Athyrium Filix- jemina (L.) Bernh., or 
Lady Fern, is also popularly ascribed with taenia- 
fuge properties. Kiirsten (Pharm. J., 1891) found 
in it pannic acid (or pannol) which is closely re- 
lated to filicic acid; it differs in being soluble in 
strong alcohol and in not yielding isobutyric acid 
on hydrolysis. Under the name of inkomankomo or 
uncomocomo, the rhizome of Aspidium athamanti- 
cum (Hook.) Kuntze, has long been used by the 
South African Kaffirs, and has entered European 
commerce as pannum (Rhizoma Pannce). In it 
Heffter (Arch. exp. Path. Pharm., 1897, 38, 458) 



122 Aspidium 



Part I 



found three well characterized and crystallized 
principles: flavopannin, albopannin and pannol 
(pannic acid of Kiirsten). Both flavopannin and 
albopannin are powerful muscle poisons, directly 
affecting the heart. 

Extracts of male fern undergo some chemical 
change on standing which leads to a loss of filicin 
content (Goris and Metin, Bull. sc. Pharmacol., 
May, 1924). According to Pedretti {them. Abs., 
1931, 25, 4658) physiologically active amorphous 
filicic acid is changed into a crystalline inert form. 

The rhizomes of other species of fern are fre- 
quently substituted for the official, and in the 
dried state it is difficult to distinguish them. The 
varying results reported by physicians, when using 
this drug, are no doubt due to use of spurious 
male fern, or old rhizomes and stipe bases which 
are devoid of any greenish color internally. 

In collecting male fern, all the black, discolored 
portions should be cut away, the fibers and scales 
separated, and only the sound green parts pre- 
served. Most of the drug is gathered in this coun- 
try, especially in New Hampshire. Some supplies 
of Male Fern from Dryopteris Filix-mas have 
been imported from India. 

Description. — "Unground Aspidium occurs as 
unpeeled or peeled, entire or longitudinally split, 
rhizomes with attached bases of stipes, or as sep- 
arate pieces of rhizome and stipes. The rhizome is 
6 to 15 cm. in length and 3 to 4 cm. in diameter, 
cylindraceous and nearly straight, or curved and 
tapering toward one end, usually split longitudi- 
nally and showing large, angular stipe-scars, in 
which the ends of vascular bundles are often visi- 
ble, and occasionally, adhering feathery masses or 
reddish brown ramenta. The stipes are nearly 
cylindrical, but tapering toward one end, nearly 
straight or somewhat curved, 3 to 5 cm. in length, 
and up to about 10 mm. in thickness; externally 
they are usually weak reddish brown to brownish 
gray, or, if peeled, light brown to weak yellow; 
the fracture is short. The transversely fractured 
surface is pale green to weak greenish yellow or 
brown, is spongy, and exhibits an interrupted 
circle of from 2 to 13 vascular bundles. The odor 
is slight. The taste is at first sweetish and astrin- 
gent, then bitter and acrid." U.S.P. For histology 
see U.S.P. XV. 

Standards and Tests. — Aspidium contains 
not more than 2 per cent of foreign organic 
matter, and not more than 3 per cent of acid-in- 
soluble ash. U.S.P. 

Assay. — An ether extract of 40 Gm. of 
aspidium is prepared and assayed as directed 
under Aspidium Oleoresin. U.S.P. 

Adulterants. — Powdered althea leaves have 
been used as an adulterant of powdered aspidium, 
giving the light-green tint indicative of a good 
quality of drug. At other times the powder is said 
to have consisted entirely of the chaff and other 
inert material which the Pharmacopeia directs 
should be rejected. Kraemer reported that much 
of the aspidium formerly in the American market 
consisted of the large rhizomes of Osmunda Clay- 
toniana. This substitute has been frequently 
offered on the American market. Capelle (Apoth.- 
Ztg., 1907, p. 433) discussed the characteristics 
"of genuine aspidium and the differentiation of 



related species. The most recently offered sub- 
stitute has been the rhizomes of the Christmas 
Fern, Polystichum achrostichoides (Michx) 
Schott. 

Constituents. — The activity of male fern de- 
pends on the presence of a number of related 
compounds. These compounds include those desig- 
nated as amorphous filicic acid, crystalline filicic 
acid (also called filicin and filicinic acid), filic 
acid, aspidinin, albaspidin, aspidin, aspidinol, 
flavaspidinic acid, and filmaron. A green fixed oil, 
a volatile oil, sugar, starch, resin and wax are 
other substances which have been reported to be 
present. Unfortunately, there is some confusion 
in the naming of the compounds and several dif- 
ferent chemical formulas have been assigned to 
some of them, hence their exact chemical rela- 
tionship is uncertain. It does appear, however, 
that most of these substances are derivatives of 
a methyl or a dimethyl-phloroglucinol. Robertson 
and Sandrock (/. Chem. S., 1933, p. 819) verified, 
through synthesis, that aspidinol, the simplest 
phenolic constituent of the drug, is a monomethyl 
ether of C-methylphloro-M-butyrophenone. The 
same investigators (ibid., p. 1617) synthesized 
filicinic acid (earlier shown to be a decomposition 
product of several aspidium constituents) and 
verified its formula as l:l-dimethylcyclohexane- 
2:4:6-trione. For a review of the reports on the 
constituents of aspidium, see Pabst and Bliss 
(/. A. Ph. A., 1932, 21, 431). 

Pabst and Bliss state that for purposes of 
standardization of aspidium and its oleoresin by 
chemical methods the active constituents have 
been assumed to be crude filicic acid. The latter 
is actually a mixture of complex composition and 
no reliable methods have been devised by which 
each of the constituents may accurately be de- 
termined. It is further claimed that crude filicic 
acid is accompanied by inert constituents in vary- 
ing and unknown amounts. 

Uses. — Because of its rapid deterioration pow- 
dered aspidium is rarely employed. The more 
stable oleoresin, prepared as soon as the drug is 
harvested, is the preferred dosage form. For uses 
of aspidium see under Aspidium Oleoresin. E 

Dose, of powdered aspidium rhizome, 4 to 8 
Gm. (approximately 1 to 2 drachms). 

ASPIDIUM OLEORESIN. U.S.P. 
(B.P., LP.) 

Extract of Male Fern, Male Fern Oleoresin, 
[Oleoresina Aspidii] 

"Aspidium Oleoresin yields not less than 24 per 
cent of crude filicin." U.S.P. 

The B.P. requires that the Extract of Male 
Fern contain 25.0 (limits, 24.0 to 26.0) per cent 
of crude filicin. The LP. requires not less than 
25.0 per cent and not more than 26.0 per cent of 
filicin. 

B.P. Extract of Male Fern; Extractum Filicis. LP. 
Oleoresina Filicis Malis. Liquid Extract of Male Fern; 
Oil of Fern. Oleoresina Filicis; Extractum (Oleum) Filicis 
Maris; Extractum Filicis Maris ^Ethereum. Fr. Extrait de 
fougere male; Extrait oleo-resineux de fougere male; 
Extrait ethere de fougere male. Ger. Farnextrakt. It. 
Estratto di felce Maschio etereo. Sp. Extracto de 
helecho macho, etereo; Oleorresina de Aspidio. 

Place 500 Gm. of aspidium, recently reduced to 



Part I 



Aspidium Oleoresin 123 



coarse powder, in a cylindrical glass percolator 
provided with a stopcock, and with a cover and a 
receptacle arranged for safe use of volatile liquids. 
Pack the powder firmly, and percolate slowly with 
ethyl oxide added in successive portions until the 
drug is exhausted. Recover the greater part of 
the ethyl oxide from the percolate by distillation 
on a water bath and, having transferred the resi- 
due to a dish, allow the remaining ether to evapo- 
rate spontaneously in a warm place remote from 
a naked flame. U.S.P. 

The process of extraction in the B.P. is essen- 
tially the same as that in the U.S. P., except that 
after the ether has been evaporated the extract 
is assayed and sufficient arachis oil or other suit- 
able official fixed oil is added to produce an ex- 
tract of the required strength. 

This is the only preparation of male fern which 
should be used; in its making aspidium which is 
internally green in color and recently collected 
should be employed. The oleoresin is a thick, dark 
green liquid having the odor of the fern and a 
nauseous, bitter and somewhat acrid taste. It 
usually contains a granular deposit of crystalline 
material which is regarded as an active ingredient 
and should not be separated. According to Hayes, 
when an absolutely dry root and an anhydrous 
ether (containing but little alcohol) of a specific 
gravity below 0.728 are used, the oleoresin re- 
mains clear. Aspidium oleoresin has been some- 
times found in the market containing noticeable 
proportions of copper, and in many cases it is 
colored green artificially. 

Description. — "Aspidium Oleoresin is a dark 
green, thick liquid, usually depositing a granular, 
crystalline substance, which must be thoroughly 
mixed with the liquid portion before use. Aspidium 
Oleoresin is insoluble in water; it is soluble in 
alcohol and in ether. Not less than 85 per cent of 
the Oleoresin is soluble in petroleum benzin. The 
specific gravity of Aspidium Oleoresin is not less 
than 1.00." U.S.P. The B.P. and the LP. both 
require the oleoresin to have a refractive index, 
at 40°, of not less than 1.492. 

The requirement of the U.S.P. that not less 
than 85 per cent of the oleoresin shall be soluble 
in petroleum benzin is to exclude adulteration 
with castor oil, which is only slightly soluble in 
petroleum benzin. The presence of castor oil is 
especially undesirable because it increases the 
absorption of aspidium. 

Assay. — After warming the aspidium oleoresin 
on a water bath and stirring it until thoroughly 
mixed, a sample of 3 Gm. is dissolved in ether, 
and the phenolic and acidic constituents compris- 
ing "crude filicin" removed by shaking the ether 
with portions of 3 per cent barium hydroxide so- 
lution. The barium hydroxide solutions are filtered, 
combined, acidified to liberate the phenolic and 
acidic substances, and these extracted with ether. 
After filtration the ether solution is evaporated 
and the residue of crude filicin dried at 105° for 
2 hours and weighed. U.S.P. 

The B.P. and LP. assays are practically the 
same as that of the U.S.P. 

Attempts have been made to standardize not 
only aspidium but other anthelmintics as well by 
biological methods. Sollmann (/. Pharmacol., 



1918, 12, 129) proposed use of the earthworm 
for this purpose. His method is as follows: The 
worms, which are kept in damp leaf mold before 
being used, are washed with tap water and five of 
them are placed in beakers containing 100 ml. of 
tap water, to which are added varying quantities 
of the anthelmintic substance. After 24 hours the 
mobility of the worms is observed. Munch recom- 
mends, for the purpose of determining life in the 
worm, stimulation with faradic current. He found 
close agreement, in his tests with aspidium oleo- 
resin, between the toxicity to worms and chemical 
assay. Other test animals which have been sug- 
gested include the ascarides of either dogs or 
pigs, various other helminths, and even goldfish. 
Carlsson and Backstrom (Chem. Abs., 1944, 38, 
2451) found that there is a linear relationship be- 
tween the potency of aspidium extracts and their 
extinction coefficient as calculated from optical 
density readings using a photoelectric instrument. 
They also reported that the activity of the ex- 
tracts may be judged by their toxicity to earth- 
worms; hexylresorcinol was used as the toxicity 
standard. For a report on the chemical and bio- 
logical standardization of aspidium oleoresin see 
Pabst and Bliss (/. A. Ph. A., 1932, 21, 431). 

Uses. — Aspidium oleoresin is used in medicine 
almost solely for expulsion of the tapeworm 
(Taenia solium or saginata, Diphyllobothrium 
latum, and Hymenolepis nana). It is not used in 
other forms of helminthiasis. It does not kill the 
parasite, but paralyzes it so that it can be washed 
out of the intestinal tract by an active purge. 

Male fern was mentioned as a vermifuge in the 
works of Dioscorides, Theophrastus, Galen, and 
Pliny, as well as by some of the earlier modern 
writers. It does not appear to have become gen- 
erally known until about 1775, when the King 
of France purchased from Madame Nouffer, 
widow of a Swiss surgeon, a secret remedy for 
tapeworm, which proved to be the powdered root 
of the male fern. As first demonstrated by Straub 
(Arch. exp. Path. Pharm., 1902, 48, 1) the prin- 
ciples of aspidium paralyze the voluntary muscles 
of higher animals, as well as the analogous con- 
tractile tissue of invertebrates. 

With adequate and careful preparation and 
management of the patient, tapeworm is elimi- 
nated in 90 per cent of cases following use of 
aspidium oleoresin. It would appear that the use 
of this drug will decrease in view of the demon- 
strated efficacy of the less toxic quinacrine. For 
purgation when aspidium oleoresin is administered 
castor oil has been employed, but its use increases 
the absorbability of the drug and adds to the 
danger of poisoning. A saline cathartic, such as 
magnesium sulfate or sodium sulfate, is prefer- 
able. Also, a fat-free diet for two days preceding 
use of aspidium is advisable. 

When aspidium oleoresin is to be administered 
a liquid diet is prescribed during the 24 hours 
preceding administration of the drug. The evening 
before the aspidium is given, the patient should 
take 15 to 30 Gm. of magnesium sulfate to empty 
the intestinal tract. In the morning a total dose of 
4 Gm. of aspidium oleoresin, in capsules or dis- 
persed in a mucilaginous vehicle, is given in one 
or two divided doses, one hour apart. A saline 



124 Aspidium Oleoresin 



Part I 



purgative is given 2 hours after the last dose; this 
is followed by a soap-suds enema 2 hours later 
to remove the scolex, should it now be free within 
the intestine. By straining this material and any 
feces passed the head may be identified. The 
therapeutic course should not be repeated in less 
than 7 to 10 days. The toxicity of aspidium ren- 
ders its use in children hazardous. 

Toxicology. — Aspidium is a violent poison, 
the relative rarity of serious symptoms from its 
use being due to its non-absorbability. When there 
is a large amount of fatty matter in the bowel, it 
may be absorbed and give rise to serious and even 
fatal poisoning (see Hernandez Morales, Puerto 
Rico J. Pub. Health Trop. Med., 1945, 21, 213; 
also Lancet, 1882). It is highly irritant and may 
produce vomiting and severe diarrhea. Stimulation 
of the spinal cord may produce tremors and tonic 
convulsions, followed by ascending depression, in- 
volvement of the medulla, respiratory failure with 
cyanosis and dyspnea. There may be headache, 
cold sweats and mental disturbances. In nearly 
half of the cases there has been disturbance of 
vision, and even blindness, which in a few in- 
stances remained permanently. According to Har- 
nack {Munch, med. Wchnschr., 1912, 59, 1941), 
the blindness is due to spasm of the retinal vessels 
and subsequent optic atrophy. Prevost and Binet 
found that in the lower animals the oleoresin, 
given hypodermically, produces violent dyspnea 
and death from arrest of the heart in systole; 
Frohner found parenchymatous nephritis in ani- 
mals fatally poisoned by it. Liver damage and 
jaundice may occur. 

Should symptoms of poisoning appear, use of 
an emetic such as mustard or zinc sulfate fol- 
lowed by vigorous catharsis with magnesium sul- 
fate is indicated. Symptomatic and supportive 
measures are required, including parenteral fluids, 
electrolytes and dextrose, demulcents for the irri- 
tated gastrointestinal tract, and stimulants, such 
as caffeine, or sedatives, such as the barbiturates, 
as indicated. 

Contraindications. — Aspidium should not be 
administered during pregnancy, nor to debilitated 
adults or children. Parenchymal cardiac, hepatic, 
and renal diseases are contraindications to its use; 
so also is any ulcerative lesion of the gastrointesti- 
nal tract. E 

Filmaron, one of the active constituents of 
aspidium, has been used as a clinical vermifuge, 
as a 10 per cent solution in castor oil. The dose 
of filmaron is 0.5 to 0.75 Gm. (approximately 7J4 
to 12 grains). 

The usual adult dose of aspidium oleoresin is 
4 Gm. (approximately 60 grains), the range being 
1 to 5 Gm. The maximum safe dose is usually 5 
Gm., and the maximum dose in a period of 1 to 2 
weeks should seldom exceed 5 Gm. For children 
the dose is 250 mg. (approximately 4 minims) 
per year of age, up to a maximum of 15 years. 
Aspidium oleoresin may be administered by 
mouth or duodenal tube, dispersed in a freshly 
prepared mucilaginous vehicle; a typical formula 
consists of aspidium oleoresin, 4 Gm.; acacia 
mucilage, 30 ml.; cinnamon or other aromatic 
water, to 45 ml. The oleoresin may also be given 



in capsules or, especially to children, on a tea- 
spoonful of sugar. 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

CAPSULES OF EXTRACT OF 
MALE FERN. B.P. 

These are defined as flexible gelatin capsules, 
the shells of which are colored black. Not less 
than 95.0 per cent and not more than 105.0 per 
cent of the prescribed, or stated, volume of ex- 
tract is required to be present in each capsule of 
average volume. B.P. 

ATROPINE. N.F., B.P, LP. 

[Atropina] 

"Atropine is an alkaloid usually obtained from 
Atropa Belladonna Linne, from species of Datura 
and Hyoscyamus (Fam. Solanacece), or produced 
synthetically. Caution. — Atropine is extremely 
poisonous." N.F. The B.P. defines Atropine as 
(±) -hyoscyamine and says that it is obtained 
from Hyoscyamus muticus L, Duboisia species, 
and other plants of the Solanacece. The LP. 
defines it as DL-tropanyl-2 -hydroxy 1-1 -phenyl- 
propionate. 

I.P. Atropinurn. Fr. Atropine. Ger. Atropin. It. Atropina. 
Sp. Atropina. 

Atropine, discovered by Yaquelin in 1809, was 
recognized as an alkaloid by Brandes in 1819. It 
does not occur in plants to any appreciable extent 
as such, but does occur as its levorotatory isomer 
hyoscyamine, from which it is prepared by 
racemization. 

Hyoscyamine, the most commonly occurring 
of the solanaceous alkaloids, and the one from 
which atropine is prepared, occurs naturally only 
as a levorotatory base. It melts at 108.5°, is 
readily soluble in chloroform, benzene or alcohol, 
less so in ether or cold water. The hydrobromide 
and sulfate are official and are described elsewhere 
in Part I. 

Belladonna root, Hyoscyamus muticus, or H. 
niger are common sources for the manufacture of 
atropine. The powdered plant material is thor- 
oughly moistened with an aqueous solution of 
sodium carbonate and extracted by percolation 
with ether or ethyl acetate. The bases are ex- 
tracted from the ether with acetic acid, the acid 
solution being shaken with ether as long as the 
ether takes up coloring matter, then precipitated 
with sodium carbonate. The precipitate of the 
bases, after washing and drying, is dissolved in 
ether, the solution dehydrated with anhydrous 
sodium sulfate and filtered. Upon concentration 
of the ether solution the bases crystallize upon 
standing, the mixture being chilled in order to 
hasten crystallization. The crude crystalline mass 
consisting of a mixture of atropine and hyoscya- 
mine, after filtering and drying, is mixed with 
one-fourth of its weight of chloroform and heated 
under a reflux condenser for 2 hours at from 116° 
to 120°. This treatment racemizes the hyoscya- 
mine into atropine. The racemization can also be 
accomplished by treating the alcohol solution of 



Part I 



Atropine 125 



the bases with some sodium hydroxide and allow- 
ing to stand until the racemization is complete as 
determined by optical measurement. The crude 
atropine is purified by solution in acetone, treat- 
ment with decolorizing carbon and, after filtration, 
the solution is concentrated and cooled by means 
of ice and salt. To hasten the crystallization the 
solution is seeded with a few crystals of atropine. 

The sulfate may be prepared from the base by 
dissolving the latter in acetone and adding just 
enough dilute sulfuric acid to furnish the neces- 
sary amount of H2SO4. 

Kraut demonstrated, in 1864, that atropine 
undergoes hydrolysis, on heating either with hy- 
drochloric acid or with barium hydroxide solution, 
into tropic acid and tropine. Ladenburg (Ber., 
1880, 13, 376) succeeded in synthesizing atropine 
from these two substances. 

Tropic acid, a homologue of mandelic acid, is 
alpha-phenyl-beta-hydroxypropionic acid, C6H5- 
CH(CH 2 OH)COOH. Tropine, also called 3-tro- 
panol, is a tertiary base containing a secondary 
alcohol group which in atropine is esterified with 
tropic acid; atropine is, accordingly, tropyltr opine. 
Tropine is of interest also because it is the parent 
substance of cocaine and most other coca alkaloids 
(for formula of tropine see under Cocaine). On 
oxidation, tropine is converted to the ketone 
tropinone. Robinson (/. Chem. S., 1917, 111, 
762), visualizing the latter as a possible starting 
compound for the production not only of atro- 
pine and hyoscyamine but cocaine, tropacocaine 
and the artificial tropeines as well, prepared tro- 
pinone by reacting succindialdehyde, methyla- 
mine, and acetone (or acetonedicarboxylic acid). 
Variants of this method have been the subject of 
many patents and a number of synthetic substi- 
tutes for atropine have been prepared utilizing 
tropinone. 

A large number of esters of tropine, to which 
the general name of tropeines has been given, have 
been synthesized. Some of these have pronounced 
toxic effects, but one (homatropine) has found 
use as a valuable substitute for atropine. 

Description. — "Atropine occurs as white crys- 
tals, usually needle-like, or as a white, crystalline 
powder. Its saturated solution is alkaline to phe- 
nolphthalein T.S. It is optically inactive, but 
usually contains some levorotatory hyoscyamine. 
One Gm. of Atropine dissolves in 460 ml. of water, 
in 2 ml. of alcohol, in about 27 ml. of glycerin, in 
1 ml. of chloroform, and in about 25 ml. of ether. 
One Gm. of it dissolves in 90 ml. of water at 80°. 
Atropine melts between 114° and 116°." N.F. 

Standards and Tests. — Identification. — (1) 
A yellow residue is obtained on evaporating a mix- 
ture of 10 mg. of atropine and several drops of 
nitric acid to dryness on a water bath. An intense 
violet color is produced on adding a few drops of 
alcoholic potassium hydroxide T.S. and a frag- 
ment of potassium hydroxide to the cooled residue 
(hyoscyamine and scopolamine respond similarly, 
but other alkaloids obscure the effect). (2) A 
lusterless precipitate forms on adding gold chlo- 
ride T.S. to a 1 in 50 solution of atropine in di- 
luted hydrochloric acid (hyoscyamine yields a lus- 
trous precipitate). Residue on ignition. — Not over 



0.1 per cent. Readily carbonizable substances. — A 
solution of 200 mg. of atropine in 5 ml. of sul- 
furic acid has no more color than matching fluid 
A; this solution is colored no more than light yel- 
low on adding 0.2 ml. of nitric acid. Other alka- 
loids. — Platinic chloride T.S. produces no pre- 
cipitate when added to a 1 in 75 solution of atro- 
pine in N/ 15 hydrochloric acid. Addition of 2 ml. 
of ammonia T.S. to a 5 ml. portion of the same 
solution does not produce an immediate turbidity. 
Limit of hyoscyamine. — The angular rotation of 
a solution of 1 Gm. of atropine, previously dried 
at 105° for 1 hour, in enough 50 per cent (by 
weight) alcohol to make 20 ml. of solution at 25°, 
and polarized in a 200-mm. tube, does not exceed 
—0.70°. N.F. 

The detection of small quantities of atropine 
has been the subject of a number of investiga- 
tions; a useful physiological test consists in plac- 
ing the liquid to be tested in the eye of a cat, or 
other animal, when, if the alkaloid be present, 
dilatation of the pupil will occur. Vitali's test, in 
which alcoholic potassium hydroxide solution is 
added to atropine which has been oxidized with 
nitric acid, is said to produce a violet color with 
as little as 0.4 microgram of the alkaloid. This is 
one of the U.S. P. tests for identification. For 
microchemical reactions of atropine see Kleibs 
(Chem. Abs., 1939, 33, 9201). 

Uses. — The effects of atropine upon the system 
are due to an action on certain medullary and 
higher nerve centers, and a paralysis of secretory 
glands and smooth muscle fibers innervated by 
the parasympathetic division of the autonomic 
nervous system (see monograph on Anticholinergic 
Agents, in Part II, for comparison with related 
compounds and the pharmacological basis for 
their action). 

Absorption-Excretion. — The absorption of 
atropine is rapid. Within a few hours about one- 
third of the dose is excreted by the kidney. The 
remainder is hydrolyzed into tropine and tropic 
acid. Tropine is related to ecgonine (see above), 
the basic constituent of cocaine (Paul and Rhom- 
berg, J. Iowa M. Soc, 1945, 35, 167). 

Peripheral Action. — The parasympathetic 
nerves carry impulses to numerous viscera, among 
them being: the nerves for the salivary glands, 
the secretory glands of the nasal and pharyngeal 
mucous membranes and the bronchial tree and 
stomach, the vagus nerve, which carries inhibitory 
impulses to the heart and motor fibers to the 
bronchi and a portion of the intestinal tract, and 
the oculomotor nerve, which supplies the sphincter 
pupillae and ciliary muscle. In addition, atropine 
exerts an antispasmodic effect on smooth muscle 
of the gall bladder and biliary ducts, as well as 
on the smooth muscle of viscera supplied by the 
sacral parasympathetic ganglia, as the ureter, 
detrusor muscle of the urinary bladder, and, to a 
slight extent, the uterine muscle. Also, the cho- 
linergic nerves supplying the sweat glands are 
inhibited by atropine. The action of atropine is, 
therefore, as extensive and complex as are the 
effects of the parasympathetic system which it 
blocks. In general it is the muscarinic effects of 
acetylcholine but not its nicotinic responses which 



126 Atropine 



Part I 



are inhibited by atropine. In the presence of atro- 
pine, nerve stimulation releases acetylcholine but 
the effector cell fails to respond. Where the nerve 
endings are within the cell, as seems to be the case 
in the intestine and urinary bladder, atropine fails 
to block the effects of stimulation of the para- 
sympathetic nerves, but it blocks the effects of 
injected acetylcholine (see Fulton, Physiology of 
the Nervous System, 1938). 

Central Action. — The central effects of atro- 
pine may be attributed to central stimulation of 
the vagus nerve and of the respiratory center. 
There is also a primary depressant action on cer- 
tain motor mechanisms. Toxic doses, however, 
after causing restlessness, disorientation, and de- 
lirium, ultimately will produce paralysis of the 
medulla. Rarely, atropine is used as a respiratory 
stimulant in doses of 0.5 to 1.5 mg. (approxi- 
mately Vi2o to Vio grain), which should not be 
repeated lest paralysis occur. Atropine is bene- 
ficial in labyrinthine seasickness, but Holling et al. 
(J.A.M.A., 1944, 125, 457) found it inferior to 
scopolamine. Alexander and Portis (Psychosom. 
Med., 1944, 6, 191) used atropine in the prophy- 
lactic management of hypoglycemic fatigue but 
its efficacy is questionable. Some features of both 
the arteriosclerotic and postencephalitic forms of 
paralysis agitans, or parkinsonism, are improved 
by its use. Doses as large as 5 mg. (approximately 
V12 grain) are employed to improve the tremor, 
rigidity, salivation, oculogyric crises, etc. Some- 
times it is used in conjunction with amphetamine 
sulfate. From time to time various atropine-con- 
taining plants have enjoyed a popular vogue in 
such therapy. Often these effects have been at- 
tributed to some peculiar character of drugs 
grown in a particular locality — as the Bulgarian 
belladonna — but it is now well established that 
it is an action inherent to atropine and probably 
other related alkaloids. The most plausible ex- 
planation of this action is offered by the experi- 
ments of Pollock and Davis {Arch. Neurol. 
Psychiat., 1930. 23, 303) who observed that in 
decerebrate cats atropine diminishes the rigidity 
depending upon reflexes arising in the muscle 
itself. 

Ophthalmic Action. — In ophthalmology atro- 
pine is used both for dilating the pupil and for 
paralyzing the muscles of accommodation. Its 
action is so slow and persistent that where only 
temporary effects are desired, as, for example, in 
the fitting of glasses, it has been largely aban- 
doned for more rapidly acting drugs, but in in- 
flammatory conditions of the eye, as in iritis, 
keratitis, etc., the very persistence of its effect is 
desirable. For this purpose one or two drops of a 
1 per cent solution may be instilled into the eye 
at such intervals as are found to be necessary. 
The same purpose may be accomplished by in- 
serting beneath the eyelid small gelatin disks con- 
taining atropine (see Lamellce of Atropine'). The 
mydriatic effect may last for ten days, though 
the cycloplegic action remains only five days. It 
is important to test the intraocular tension before 
its instillation in order that glaucoma will not be 
produced. Neblett (South. Med. & Surg., 1945. 
107, 81) has called attention to this possible side 
"effect in patients using atropine for gastrointesti- 



nal tract disorders or in arthritis in conjunction 
with neostigmine administration. 

Respiratory Effects. — Atropine is used to 
check the rhinorrhea of acute rhinitis and of hay 
fever, as well as to diminish secretions in the 
entire respiratory tract when given as part of pre- 
anesthetic medication. It has been used in bron- 
chial asthma, but it is less effective than epi- 
nephrine in its relaxation of the bronchi and 
bronchioles. 

Cardiac Action. — The drug causes accelerated 
heart rate by blocking vagal impulses at the pace- 
maker or sinoauricular node. However, small doses 
(less than 1 mg., approximately Yao grain; may 
slow cardiac action by central vagal stimulation 
(McGuigan, J. A.M. A., 1921, 66, 1338). It is 
useful in preventing vagal syncope with brady- 
cardia as a result of hyperactive carotid sinus 
reflexes as described by Nichol and Strauss (Am. 
Heart J., 1943, 25, 746). It counteracts the 
bradycardia induced by pilocarpine. In complete 
heart block large doses intravenously (2 mg., ap- 
proximately Vso grain) may be beneficial. Its use 
hypodermically in doses of 0.6 or 0.8 mg. (ap- 
proximately ^oo or %o grain) is recommended by 
Gilbert (Modern Concepts of Cardiovascular Dis- 
ease, 1946, 15, No. 6) immediately on diagnosis 
of coronary thrombosis in order to abolish reflex 
arterial constriction, mediated by the vagus nerve, 
in the uninvolved myocardium. Atropine produces 
peripheral vasodilatation in the blush area by 
means of a mechanism not fully understood. 

Gastrointestinal Tract. — Atropine has an 
exceedingly complex action upon the gastrointesti- 
nal tract and its associated glands. It inhibits the 
flow of saliva in doses as small as 0.5 mg. (ap- 
proximately Yno grain). A similar dose was said 
by Henderson and Sweeten (Am. J. Digest. Dis., 
1943, 10, 241) to decrease psychic (vagal) gastric 
secretion more than that due to the hormone 
gastrin, while a dose of 1.2 mg. (approximately Yso 
grain) will abolish continuous secretion except 
that seen in some cases of peptic ulcer. Nocturnal 
gastric secretion is diminished by atropine, ac- 
cording to Means (Surgery, 1943, 13, 214), as 
are also free and total acidity in both normal and 
ulcer patients. In general, muscular tonus and 
peristalsis are decreased by its action, but the 
effect depends upon the existing tonus and degree 
of movements as well as the dose. Henderson and 
Sweeten (loc. cit.) found that in pylorospasm of 
infants a dose of 0.065 mg. (approximately a /looo 
grain) before feedings may give some relief. It 
is believed that atropine decreases the tonus of 
the small intestine and decreases the motility in 
the colon, where it antagonizes the hypertonicity 
of morphine. The intestinal glands and the forma- 
tion of bile are unaffected by atropine, as is the 
production of pancreatic secretions, since the 
latter is formed in response to the hormone 
secretin. 

Biliary and Urinary Tracts. — Other effects 
of atropine on smooth muscle bring about its use 
in conjunction with morphine in biliary colic and 
ureteral colic. Its inhibition of tonus of the 
detrusor muscle of the urinary bladder has led to 
its use in treating some cases of nocturnal 
enuresis. It has been used in dysmenorrhea, but 



Part I 



Atropine Sulfate 127 



probably is of little value. Locally, atropine in 
the form of an ointment and the belladonna plas- 
ter is used in various painful conditions, but this 
use does not seem rational. S 

Toxicology. — Atropine poisoning may occur 
from the ingestion of any of the numerous plants 
of which it is the active principle, most frequently, 
however, from either belladonna or the widespread 
stramonium. Severe poisoning may follow external 
applications. The symptoms are dryness of the 
throat, dilatation of the pupil, rapid and hard 
pulse, hurried respiration, warm and dry skin, 
flushed face, and frequently a scarlatiniform rash. 
The most striking symptom is the peculiar de- 
lirium. In the earlier stages this manifests itself 
simply by profuse and incoherent talkativeness; 
later there is complete confusion, often with hal- 
lucinations, sometimes maniacal in character. 
After large doses a stage of depression may de- 
velop, with stupor, rapid weak pulse, and respira- 
tory failure. Though the condition is alarming, 
recovery is usual. Alexander, Morris and Eslick 
{New Eng. J. Med., 1946, 234, 258) report the 
complete recovery of a patient severely poisoned 
by the ingestion of 1 Gm. of atropine sulfate 
orally. In case of doubt as to diagnosis, instilla- 
tion of a drop or two of urine from the patient 
into the eye of a cat will produce dilatation of 
the pupil, if enough atropine is present. Dameshek 
demonstrated that in atropine poisoning the usual 
sweating, salivation, etc., following acetyl-P- 
methylcholine chloride administration in doses 
of 10 to 30 mg. (approximately Yq to Yi grain) is 
absent. Atropine may cause fever, in children 
particularly, by causing dryness of the skin and 
inhibiting heat loss by evaporation. 

In the treatment, after emptying the stomach 
with the stomach tube (the dry mucosa requires 
lubrication) or an emetic, 1.2 ml. (approximately 
20 minims) of compound iodine solution should 
be given as the best chemical antidote. Morphine 
may be used to quiet the delirium, but there is 
danger of respiratory paralysis, and cautious ad- 
ministration of the barbiturates is recommended. 
Pilocarpine, the physiological antagonist, should 
be given in doses of 5 mg. (approximately Y12 
grain) until the mouth becomes moist. Respira- 
tory failure is treated with oxygen and carbon 
dioxide inhalation and by the use of caffeine. Ade- 
quate fluid intake is important. 

Dose. — The usual hypodermic dose of atropine 
(as sulfate) is 0.4 mg. (approximately Yiso grain) ; 
the dose by mouth is 0.6 mg. (approximately Yioo 
grain), although in serious cases these amounts 
may be much exceeded. On the other hand in sus- 
ceptible persons, 0.6 mg. (approximately Yioo 
grain) will produce decided dryness of the throat, 
and 1.2 mg. (approximately Ym grain) is alleged 
to have caused toxic symptoms. As atropine itself 
is nearly insoluble, the sulfate is preferred. For 
application to the sound skin, an ointment may be 
made by rubbing 65 mg. (approximately 1 grain) 
of the alkaloid first with 0.25 ml. (approximately 4 
minims) of alcohol, and then with 4 Gm. (approxi- 
mately 1 drachm) of lard. The ointment of bella- 
donna is, however, usually preferred. 

When solution of atropine sulfate (1 or rarely 
2 per cent) is used for dilating the pupil, it may 



be dropped into the eye within the lower lid, or 
introduced by means of minute circular disks of 
gelatin, made by mixing the solution with gelatin 
and evaporating so as to produce a thin film, which 
is to be cut into circular pieces. (See Lamella of 
Atropine.) An Eye Ointment of Atropine (Ocu- 
lentum Atropines) of the B.P. contains 1 per cent 
of atropine sulfate. 

Solutions of atropine or its salts are very prone 
to have developed in them a fungous growth with 
consequent decomposition of the alkaloid; thus 
Simon (J. A.M. A., 1915, 64, 705) showed that a 
solution of atropine may become entirely inert in 
three days. 

Dose, of atropine, 0.3 to 1.2 mg. (approximately 
Y200 to Y50 grain) . 

Storage. — Preserve "in tight, light-resistant 
containers." N.F. 



ATROPINE SULFATE. 
U.S.P. (B.P.) LP. 

Atropinium Sulfate, [Atropinae Sulfas] 



H 
HjC— C 



1+ 

HNCH 3 



H 2 C— C- 
2 H 



•CH, 

I * I 

CH-O-CO-CH 
I 

■CH- 



CH 2 0H 



-\J 



SOf . H,0 



"Caution. — Atropine Sulfate is extremely poi- 
sonous." U.S.P. 

B.P. Atropine Sulphate; Atropinae Sulphas. I. P. Atro- 
pini Sulfas. Atropinum Sulfuricum; Sulfas Atropicus. 
Fr. Sulfate d'atropine; Sulfate neutre d'atropine. Ger. 
Atropinsulfat ; Schwefelsaures Atropin. It. Solfato di 
atropina. Sp. Sulfato de atropina. 

Atropine sulfate may be prepared by the inter- 
action of a solution of atropine in ether and of 
sulfuric acid in alcohol. For details of the for- 
merly official method see U.S.D., 20th ed., p. 208. 

Description. — "Atropine Sulfate occurs as 
colorless crystals, or as a white, crystalline pow- 
der. It is odorless. It effloresces in dry air, and is 
affected by light. One Gm. of Atropine Sulfate 
dissolves in 0.5 ml. of water, in 5 ml. of alcohol, 
and in about 2.5 ml. of glycerin. One Gm. dis- 
solves in 2.5 ml. of boiling alcohol. Atropine Sul- 
fate, dried at 105° for 4 hours, melts at a tem- 
perature not lower than 188°." U.S.P. The B.P. 
gives the melting point of atropine sulfate, when 
dried at 135° for 15 minutes, as between 191° 
and 196°; the LP. specifies a melting range of 
191° to 195° after drying at 110° for 4 hours. 

Standards and Tests. — Identification. — Atro- 
pine sulfate responds to the identification tests 
given under atropine, and a 1 in 20 solution of the 
salt also responds to tests for sulfate. Acidity. — 
Not more than 0.3 ml. of 0.01 N sodium hydroxide 
is required to neutralize a solution of 1 Gm. of 
atropine sulfate in 20 ml. of water, using methyl 
red T.S. as indicator. Water. — Not over 4 per 
cent, when dried for 4 hours at 105°, or deter- 
mined by the Karl Fischer method. Residue on 
ignition. — Not over 0.2 per cent. Readily car- 
bonizable substances. — This test is identical with 
the corresponding test described under Atropine. 



128 Atropine Sulfate 



Part I 



Other alkaloids. — This test is similar to the cor- 
responding one described under Atropine, except 
that a 1 in 60 solution of atropine sulfate is used. 
Limit of hyoscyamine. — When the test is per- 
formed as described under atropine the angular 
rotation does not exceed — 0.60°. U.S.P. 

Uses. — The effects of the salt on the system 
are precisely the same as those of atropine, and 
it may be used in the same dose. Its great advan- 
tage over the alkaloid is its solubility in water. 

The U.S. P. gives the usual dose as 0.5 mg. (ap- 
proximately ^120 grain), and the range as 0.3 to 
1.2 mg. Topically a 1 to 2 per cent solution is used. 

Storage. — Preserve "in tight, light-resistant 
containers." U.S.P. 

Off. Prep.— Atropine Sulfate Tablets, U.S.P., 
B.P.; Morphine and Atropine Sulfate Tablets, 
N.F.; Lamellae of Atropine; Eye Ointment of 
Atropine; Eye Ointment of Atropine with Mer- 
curic Oxide, B.P. 



ATROPINE SULFATE TABLETS. 
U.S.P. (B.P., LP.) 

[Tabellae Atropinae Sulfatis] 

"Atropine Sulfate Tablets contain not less than 
93 per cent and not more than 107 per cent of the 
labeled amount of (Ci-H23N03)2.H2SO-iH20 for 
tablets of 20 mg. or more; and not less than 90 
per cent and not more than 110 per cent of the 
labeled amount for tablets of less than 20 mg." 
US. P. The corresponding limits of the B.P. and 
LP. are 90.0 and 110.0 per cent, regardless of the 
content of atropine sulfate. 

B.P. Tablets of Atropine Sulphate; Tabellae Atropine 
Sulphatis. LP. Compressi Atropini Sulfatis. Sp. Tabletas 
de Sulfato de Atropina. 

Tests. — Identification. — (1) When 1 drop of a 
filtered solution of the tablets, representing 1 mg. 
of atropine sulfate in 10 ml., is instilled into the 
eye of a cat or other animal, the pupil shows 
noticeable dilation within 2 hours. (2) Atropine 
alkaloid obtained from the tablets responds to 
identification test (1) under Atropine. (3) A 
filtered solution of the tablets responds to tests 
for sulfate. U.S.P. 

Assay. — An aqueous extract of the tablets, pre- 
pared with the aid of diluted sulfuric acid and rep- 
resenting 60 mg. of atropine sulfate, is made alka- 
line with ammonia and the liberated atropine 
extracted with chloroform. Following evaporation 
of the chloroform, the last traces of which are 
expelled with the aid of neutralized alcohol, the 
atropine is estimated by a residual titration using 
20 ml. of 0.02 N sulfuric acid, the excess of acid 
being titrated with 0.02 N sodium hydroxide, using 
methyl red T.S. as indicator. Each ml. of 0.02 N 
sulfuric acid represents 6.949 mg. of (C17H23- 
N03)2.H2S04.H20. A variant of this method is 
permitted if the tablets contain a very small 
amount of atropine sulfate. U.S.P. 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 

Usual Sizes. — In V200, -Kso, Vno, Vioo and Ho 
grain (approximately 0.3, 0.4, 0.5, 0.6, and 1.2 
mg.) tablets. 



EYE OINTMENT OF ATROPINE. 
B.P. 

Oculentum Atropinae 

This ointment contains, unless another strength 
is specified, 1 per cent of atropine sulfate in a 
base of 10 parts of wool fat and 90 parts of 
yellow soft paraffin; the atropine sulfate is dis- 
solved in the smallest quantity of water for injec- 
tion before incorporating it with the base (see 
Eye Ointments for further information). 

EYE OINTMENT OF ATROPINE 
WITH MERCURIC OXIDE. B.P. 

Oculentum Atropinae cum Hydrargyri Oxido 

This ointment contains, unless other concen- 
trations are specified, 1 per cent of atropine sul- 
fate and 1 per cent of yellow mercuric oxide in 
a base of 10 parts of wool fat and 90 parts of 
yellow soft paraffin; the atropine sulfate is dis- 
solved in the smallest quantity of water for in- 
jection before incorporating it with the base (see 
Eye Ointments for further information). For the 
therapeutic role of the ingredients of this oint- 
ment see under both Atropine and Yellow Mer- 
curic Oxide Ointment. 

INJECTION OF ATROPINE 
SULPHATE. B.P. (LP.) 

Injectio Atropinae Sulphatis 

The injection is a sterile solution of atropine 
sulfate in water for injection, the solution being 
sterilized by dissolving in it 0.2 per cent w/v of 
chlorocresol or 0.002 per cent w/v of phenyl- 
mercuric nitrate and heating it in its final con- 
tainers at 98° to 100° for 30 minutes, or by 
filtration through a bacteria-proof filter. No rubric 
is provided. The LP. requires Injection of Atro- 
pine Sulfate {Injectio Atropini Sulfatis) to con- 
tain not less than 85.0 per cent and not more than 
110.0 per cent of the labeled amount. 

LAMELLiE OF ATROPINE. B.P. 

Lamellae Atropinae 

Discs of Atropine. Lamellae Ophthalmicae cum Atropino; 
Gelatina Atropini. Fr. Disques d'atropine. Sp. Discos 
oftalmicos con atropina. 

Lamellae of atropine are discs of gelatin with 
glycerin, each weighing about 1.3 milligrams (V»o 
grain) and containing 0.065 milligram (^000 
grain) of atropine sulfate, unless another amount 
of the active ingredient is specified. The method 
of preparation is discussed under Lamellce. 



AUROTHIOGLUCOSE. 

Gold Thioglucose 



X.F. 



1 1 

AuS.CH.HCOH.HOCH.HCOH.HC.CH.2OH 

"Aurothioglucose, dried over sulfuric acid for 
24 hours, yields not less than 47.7 per cent and 
not more than 53.0 per cent of Au. It contains 
not more than 5 per cent of sodium acetate as 
a stabilizer." N.F. 

Solganal (Schering). 

Aurothioglucose may be prepared by the inter- 



Part I 



Bacillus Calmette-Guerin Vaccine 129 



action of aqueous solutions of gold bromide and 
thioglucose, in the presence of sulfur dioxide; the 
aurothioglucose is precipitated from the reaction 
medium by addition of alcohol and is subsequently 
purified by solution in water and precipitation 
with alcohol. As indicated in the official defini- 
tion, it contains sodium acetate as a stabilizer. 

Description. — "Aurothioglucose occurs as a 
yellow powder. It is odorless or nearly so and is 
stable in air. An aqueous solution is unstable on 
long standing. The pH of a solution of Auro- 
thioglucose (1 in 100) is about 6.3. Aurothioglu- 
cose is freely soluble in water. It is practically 
insoluble in acetone, in alcohol, in chloroform, 
and in ether." N.F. 

Standards and Tests. — Identification. — (1) 
The glucosazone prepared from aurothioglucose 
melts between 189° and 194°. (2) A portion of 
the filtrate obtained in the assay forms with 
barium chloride T.S. a heavy white precipitate. 
Specific rotation. — Not less than +65° and not 
more than +75° when determined in an aqueous 
solution containing 100 mg. of aurothioglucose, 
previously dried over sulfuric for 24 hours, in 
each 10 ml. Loss on drying. — Not over 1 per cent 
when dried over sulfuric acid for 24 hours. N.F. 

Assay. — About 1 Gm. of aurothioglucose, 
previously dried over sulfuric acid for 24 hours, 
is dissolved in water, reacted with nitric acid, and 
the precipitate of metallic gold thereby obtained 
is filtered off, washed with hot water, dried, 
ignited, and weighed. N.F. 

Uses. — This water-soluble, oil-insoluble or- 
ganic compound with a gold-to-sulfur linkage is 
injected intramuscularly as a suspension in sesame 
oil for treatment of active rheumatoid arthritis 
and nondisseminated lupus erythematosus. The 
pharmacology, toxicology, and uses of gold com- 
pounds are discussed under Gold Sodium Thio- 
malate, in Part I. 

The slow absorption of gold from aurothio- 
glucose injection decreases incidence of untoward 
reactions (Dawson et at., Trans. A. Am. Physi- 
cians, 1941, 56, 330). Objective or subjective im- 
provement in 88 per cent of 122 cases of rheu- 
matoid arthritis, with toxic effects in only 11 per 
cent of these, resulted from use of aurothioglu- 
cose (Cohen and Dubbs, New Eng. J. Med., 1943, 
229, 773). A dose of 200 mg. weekly was found 
to be more effective than 100 mg., but the inci- 
dence of toxic effects was too high (Ellman et al., 
Brit. M. J., 1940, 2, 314). A comparison of the 
results of treatment of 102 early cases (within 
one year of onset) of rheumatoid arthritis with 
500 mg. or more of gold salt, usually aurothio- 
glucose or gold sodium thiomalate, with 83 cases 
not receiving gold therapy, reported by Adams 
and Cecil {Ann. Int. Med., 1950, 33, 163), re- 
vealed the following : complete remission occurred 
in 66 per cent of patients receiving gold, in con- 
trast with 24 per cent of the other group (who 
were treated by other methods) ; no improvement 
was reported by 3 per cent of patients receiving 
gold and 18 per cent of those in the other group. 
Gold therapy commenced within 6 months of the 
onset of illness resulted in complete remission in 
nearly 80 per cent of the patients but when it was 



not started until the second 6 months such favor- 
able response was observed in less than 50 per 
cent of the patients. 

Dose. — The usual dose of aurothioglucose in 
rheumatoid arthritis is 50 mg. (about % grain) 
weekly, injected intramuscularly, until a total 
dose of 1 Gm. has been given. Preferably, a dose 
of 10 mg. is given the first week, followed by 25 
mg. the second and third weeks; if no untoward 
effects appear, the full dose of 50 mg. may then 
be given, with careful observation of the patient 
(as described under Gold Sodium Thiomalate) . 
After the total of 1 Gm. (rarely 1.5 Gm.) has 
been given, maintenance doses of 50 mg. every 
2 to 4 weeks may be continued if needed and 
tolerated. Much smaller doses are employed 
initially in the often hypersensitive cases of non- 
disseminated lupus erythematosus, viz., 0.1, 0.5, 
1, 2.5, 5 and 10 mg. at intervals of 2 to 3 days, 
and then 25 mg. and eventually 50 mg. weekly. 

Storage. — Preserve "in tight, light-resistant 
containers." N.F. 



AUROTHIOGLUCOSE INJECTION. 
N.F. 

Gold Thioglucose Injection 

"Aurothioglucose Injection is a sterile suspen- 
sion of aurothioglucose, with or without a suit- 
able thickening agent, in a suitable fixed oil for 
injection, and yields an amount of aurothioglucose 
equal to not less than 90 per cent and not more 
than 110 per cent of the labeled amount of 
CeHiiAuOsS." N.F. 

Suspension Solganal in Oil (Schering). 

Assay. — A volume of injection equivalent to 
about 200 mg. of aurothioglucose is treated with 
acetone to dissolve the oil while leaving the auro- 
thioglucose and any thickening agent, such as 
aluminum stearate, as an insoluble residue. The 
insoluble material is separated by filtration, dried 
at 65°, and weighed. This is treated with water to 
dissolve the aurothioglucose, leaving the aluminum 
stearate as an insoluble residue, which is weighed 
after drying at 105°. The difference in the two 
weights represents the aurothioglucose. N.F. 

Storage. — Preserve "in either single-dose or 
multiple-dose hermetic, light-resistant containers, 
or in other suitable containers." N.F. 

Usual Sizes.— 10, 25, 50, and 100 mg. (ap- 
proximately V%, H, 2 A, and I 1 /* grains) in 1 ml. 

BACILLUS CALMETTE-GUERIN 
VACCINE. B.P. 

B.C.G. Vaccine 

The B.P. defines this vaccine as a suspension of 
living cells of an authentic strain of the bacillus 
of Calmette and Guerin, the strain being main- 
tained so as to preserve its power of sensitizing 
man to tuberculin and its relative non-pathoge- 
nicity to man and laboratory animals. The B.P. 
vaccine, which is a liquid and deteriorates rapidly, 
cannot be used more than 14 days after the com- 
pletion of its manufacture. 



130 



Bacillus Calmette-Guerin Vaccine 



Part I 



Historical. — Attenuation of a highly virulent 
bovine strain of tubercle bacillus, isolated from 
the udder of a tuberculous cow in 1902, was 
achieved by Calmette and Guerin by transplanting 
cultures of the organism at 15-day intervals on 
potato medium impregnated with beef bile and 
glycerin. After 13 years and 230 transplantations, 
a culture of the organism no longer produced 
progressive tuberculosis in susceptible animals. 
Despite the loss of virulence, the culture retained 
its original cultural and antigenic characteristics, 
including the ability to produce potent tuberculin. 
This attenuated culture was designated BCG 
(Bacillus Calmette and Guerin); all strains used 
for the production of the vaccine are traceable to 
this original culture, developed in the Pasteur 
Institute, in Paris, France. The avirulent phase of 
the culture was found to produce nodular lesions 
in animals, with no evidence of progression; it 
was also discovered that these tuberculin-positive 
animals, when infected with virulent tubercle 
bacilli, resisted to a great extent a progressive in- 
fection (Calmette, Guerin et al., La vaccination 
preventive contre la tuber culose par le BCG, 
1927, Masson & Cie. Paris). 

Preparation. — The culture used for produc- 
tion of BCG vaccine must be directly traceable 
to the Pasteur Institute of Paris. All work must 
be done in completely isolated laboratories, re- 
served for this purpose, by personnel in no way 
associated with pathogenic bacteria. The technical 
staff must be free of tuberculosis and undergo 
roentgenological examination every 3 to 6 months. 
To prepare the vaccine the BCG culture is grown 
on protein-free Sauton medium containing aspara- 
gin, glycerin, citric acid, dipotassium phosphate, 
magnesium sulfate, ferric ammonium citrate and 
water. The culture is grown at 37.5° C. for 7 
days, after which the bacillary film is collected, 
drained of excess medium and weighed. A weighed 
amount of this mass is then suspended in buf- 
fered phosphate solution, at pH 7.2, to produce a 
concentration of 0.5 to 1.5 mg. per ml. if intended 
for intracutaneous use, or 15 to 20 mg. per ml. 
if intended for multiple puncture or scarification 
use. BCG vaccine may be either a freshly pre- 
pared suspension of the organisms or it may be 
a dried culture (prepared from the frozen state) 
in which case it is suspended just prior to use. 
The volume recommended for restoration of a 
dried vaccine is determined on the basis of the 
use of the vaccine as indicated above. 

Tests. — The time required to complete the 
testing of BCG vaccine is longer than the period 
(14 days) during which the liquid vaccine may 
be used, for which reason the vaccine must be 
used before the tests have been completed. Never- 
theless, these tests must be made in order to 
complete the production protocol. Potency is de- 
termined by observation of the formation of in- 
durations or nodules in normal guinea pigs fol- 
lowing injection of 0.1, 0.01, 0.001, and 0.0001 
mg. of BCG vaccine. At the end of 2 to 3 weeks, 
the first two doses should produce definite non- 
suppurating lesions, the third dose should produce 
slight nodules, and the fourth dose should form 
no nodules. The vaccine may also be tested by 



the development of sensitivity, in guinea pigs, to 
tuberculin, following multiple puncture. In addi- 
tion, each lot must be tested in tuberculin-negative 
persons. Further, each lot must be tested for 
viable organisms (20,000,000 colonies per mg. of 
growth), safety, and for sterility. A liquid vaccine 
may be released after 24 hours on sterility test 
if no growth other than of the bacillus of Cal- 
mette and Guerin occurs. 

Uses. — Bacillus Calmette-Guerin vaccine is 
used to produce active immunization against tu- 
berculosis, especially in persons likely to be 
exposed to infection and in children. 

Increased resistance to infection was first ob- 
served by Marfan (Arch. gen. mid., 1886, 17, 
423), who noted that pulmonary tuberculosis oc- 
curred infrequently in persons who had evidence 
of healed cervical adenitis, and also by Trean 
(J.A.M.A., 1888, 10, 224), who noticed that 
Sioux Indians of Dakota with scrofulous sores 
and large glands did not as a rule have phthisis 
pulmonalis. 

The first human application of BCG vaccine 
was instigated by Weill-Halle in Paris {Bull. soc. 
med., 1925, 49, 1589). Since then it has been esti- 
mated that approximately 50 million persons of 
various ages, living in different parts of the world, 
have received the vaccine. 

Reluctance to accept BCG vaccination in the 
United States can be attributed largely to the 
tragedy in Liibeck, Germany, in which 77 of 271 
infants vaccinated died of progressive tubercu- 
losis. It was later proven by the Robert Koch 
Institute of Berlin that the vaccine used was a 
mixture of BCG and a virulent strain of tubercle 
bacilli which was kept in the same incubator as 
the BCG. For this malpractice, those responsible 
were imprisoned. It can be stated unequivocally 
that up to the present time there has been no 
evidence that BCG vaccine has produced pro- 
gressive tuberculosis in man or animals. 

Calmette and his associates originally encour- 
aged mass immunization of newborn infants by 
the oral route. Wallgren (J. A.M. A., 1928, 91, 
1876) subsequently demonstrated the superiority 
of the intracutaneous route over the oral route. 
Rosenthal et al. (J.A.M.A., 1948, 136, 73) and 
Birkhaug (Acta med. Scandinav., 1944, 117, 274) 
advocated the multiple puncture method, while 
in some countries the scarification method is 
used. 

Despite the extensive use of BCG vaccine there 
is a diversity of opinion regarding its value. This 
is largely due to a lack of adequately controlled 
investigations and to the difficulty of dissociating 
the specific protective role of BCG vaccine from 
an almost universal spontaneous decrease in the 
morbidity and mortality from tuberculosis, ante- 
dating the use of the vaccine (Aronson and Aron- 
son, J. A.M. A., 1952, 149, 334). In order to ap- 
praise as objectively as possible the specific 
values of BCG vaccine in the control of tubercu- 
losis, a joint investigation was undertaken by the 
Henry Phipps Institute of the University of 
Pennsylvania, and the Branch of Health, Bureau 
of Indian Affairs, Department of the Interior, in 
December 1935. The Indian population of eight 



Part I 



Bacitracin 



131 



different tribes, in five different geographical areas 
of the United States and Alaska, were used in 
the study. The Indian population was chosen be- 
cause of the ease of observing the Indians over 
a long period of time, their relatively low eco- 
nomic and housing conditions, and the high mor- 
bidity and mortality from tuberculosis in this 
group. Fifteen years after initiation of the study, 
12 of 1551 vaccinated persons and 65 of the 1457 
controls had died of tuberculosis, corresponding 
to rates of 0.56 and 3.32 per thousand persons 
per year, respectively (Aronson and Aronson, loc. 
cit.). The data observed in this study support the 
concept that hypersensitivity (tuberculin-positive 
reaction) developing after use of BCG vaccine is 
closely correlated with resistance to reinfection. 
Rosenthal et al. (J.A.M.A., 1948, 136, 73) con- 
cluded that the vaccine was effective in prevent- 
ing tuberculosis. Use of freeze-dried vaccine by 
the multiple puncture method of application to 
the skin is advocated (Rosenthal, ibid., 1955, 
157, 801). 

BCG vaccine is not recommended for those 
who present evidence of tuberculous infections as 
indicated by a positive tuberculin reaction. It is 
recommended for those tuberculin-negative per- 
sons whose professional duties may expose them 
to tuberculous patients or to material that may 
contain virulent tubercle bacilli and for tuberculin- 
negative persons who may be exposed to infection 
in their household. It is also recommended for 
population groups, including newborn children, 
where the morbidity and mortality from tubercu- 
losis are high, and conditions favor the spread of 
the disease. 

Dose. — The dose recommended is 0.1 ml. intra- 
cutaneously, of a suspension containing 0.5 to 1.5 
mg. per ml. For the multiple puncture method, the 
suspension used contains 15 to 20 mg. per ml. of 
growth. One drop is spread over an area 1.5 by 
2.5 cm. Thirty cutaneous punctures are made in 
this area. 

Regulations. — BCG vaccine is manufactured 
under minimum requirements of the National 
Institutes of Health, U. S. Department of Health, 
Welfare and Education. The vaccine is not com- 
mercially available, the entire supply being pro- 
duced in state and institutional laboratories. 

Storage. — Liquid BCG vaccine has an expira- 
tion date of 10 days after the date of harvesting, 
if kept constantly at 2° to 5° C. Dried BCG vac- 
cine has a dating of 6 months, if kept constantly 
at not over 5° C. 



BACITRACIN. U.S.P. 

"Bacitracin is an antibacterial substance pro- 
duced by the growth of a Gram-positive, spore- 
forming organism belonging to the Bacillus 
licheniformis group (Fam. Subtilis). It has a 
potency of not less than 40 U.S.P. Units per mg., 
except that when intended for parenteral use its 
potency is not less than 50 Units per mg. and 
when intended for the manufacture of ointments, 
tablets and troches, it may have a potency of not 



less than 30 Units per mg. Bacitracin conforms to 
the regulations of the federal Food and Drug 
Administration concerning certification of anti- 
biotic drugs. Bacitracin not intended for paren- 
teral use is exempt from the requirements of the 
tests for Pyrogen and Sterility." U.S.P. 

History. — Bacitracin is an antibiotic poly- 
peptide or complex of polypeptides elaborated in 
suitable culture media by the Tracy I strain of a 
bacillus which many authorities consider to be a 
strain of Bacillus licheniformis and others classify 
as a variant of Bacillus subtilis. The organism 
was isolated in 1945 during a study of bacterial 
contaminants in civilian wounds. Johnson et al. 
(Science, 1945, 102, 376) observed that broth 
cultures of debrided tissues from a wound on a 
child, Margaret Tracy, uniformly yielded a gram- 
positive spore-former, whereas several additional 
organisms appeared on plates prepared from the 
same tissue. This suggested that the sporulating 
species produced a substance which, in broth 
where diffusion is not so important as on agar 
plates, prevented growth of other wound con- 
taminants. Thus, a new antibiotic was discovered. 
It was named bacitracin to commemorate the 
name of the patient (Tracy), and to indicate the 
genus of organism (Bacillus). 

Production. — At first produced only in sur- 
face cultures, bacitracin now is obtained by sub- 
merged fermentation. The yield of the antibiotic 
is dependent on the composition of the nutrient 
medium, and is greatest when the ratio of carbon 
to nitrogn is about 15. Industrially, soybean meal 
(or peanut granules), starch, calcium lactate, and 
calcium carbonate are used as sources of essential 
elements. 

Recovery of the antibiotic from the fermented 
broth is accomplished by countercurrent centrifu- 
gal extraction with n-butyl alcohol and removal 
of the alcohol by distillation at reduced pressure, 
whereupon the residual aqueous concentrate is 
treated with charcoal and the slurry so formed is 
filtered. Bacitracin is in the clear filtrate. 

Description. — "Bacitracin is a white to pale 
buff powder, and is odorless or has a slight odor. 
It is hygroscopic. Its solutions rapidly deteriorate 
at room temperature. Bacitracin is precipitated 
from its solutions and is inactivated by salts of 
many of the heavy metals. Bacitracin is freely 
soluble in water. It is soluble in alcohol, in 
methanol, and in glacial acetic acid, the solution 
in the organic solvents usually showing some in- 
soluble residue. It is insoluble in acetone, in 
chloroform and in ether." U.S.P. 

Constitution. — The polypeptide character of 
bacitracin soon became apparent when chemical 
studies were initiated. Later it became clear that 
the product present in crude fermented broth is 
a complex of at least three polypeptides; these 
have been called bacitracins A, B, and C. Subse- 
quent investigation revealed the presence of a 
fourth component, bacitracin F, which is rela- 
tively inactive, if not inert, antibacterially and 
which Codington (Antibiotics Annual, 1954-1955, 
p. 1118) has suggested is a transformation product 
of the antibacterially active bacitracin A and may 
bear the following relation to it : 



132 



Bacitracin 



Part I 



C4H9- 



H 

-C— 

I 
NH, 



H 

S — CH 



/ 
C 

\ 



N— C- 
H 



-N — 
H 



Peptide 



— 2H 



Bacitracin A 



H / 

C4H9 — C — C 

I V 

NH 2 



-CH 



N — C — C— N 

& H 



Peptide 



Bacitracin F 

Newton et al. {Brit. J. Pharmacol. Chemother., 
1951, 6, 417) showed that crude bacitracin and 
ayfivin (produced by Bacillus licheniformis) are 
identical. Among the amino acid components of 
bacitracin are phenylalanine, leucine, isoleucine, 
glutamic acid, aspartic acid, lysine, histidine, 
cysteine; ammonia has also been obtained (see 
Craig et al, J. Biol. Chem., 1952, 199, 259; New- 
ton and Abraham, Biochem. J., 1953, 53, 597). 
The molecular weight is 2700 if the compound is 
a monomer; 5400 if it is a dimer. 

Stability. — Bacitracin is stable at room tem- 
perature (25°) when dry, i.e., when the content 
of moisture is less than 1 per cent; at 37° there 
is no loss of potency in 15 months, but at 56° 
and above it loses its potency rapidly. Aqueous 
solutions adjusted to a pH between 5 and 7 lose 
about 10 per cent of their initial antibacterial 
activity in from 2 to 3 months when refrigerated 
(4°) but deteriorate rapidly at room temperature. 
Bacitracin is destroyed by oxidizing agents and. 
therefore, should not be formulated with them. It 
is precipitated by the heavy metals and their salts; 
it is claimed that if the metals are low in the 
electromotive series, precipitation is accompanied 
by inactivation, but that when the metals are high 
in the electromotive series inactivation does not 
result (Baker, Drug Cosmet. Ind., 1954, 75, 764). 
Bacitracin in solution is incompatible also with 
some organic acids such as tannic acid, benzoic 
acid, and salicylic acid; also with high concentra- 
tions of sodium chloride. 

Some of the insoluble salts of bacitracin, e.g., 
zinc bacitracin and bacitracin methylenedisalicyl- 
ate, are more stable, when dry, than bacitracin and 
lack the bitterness of the natural antibiotic : being 
more palatable, these preparations would seem to 
have distinct pharmaceutical advantages. How- 
ever, more work is necessary for their complete 
clinical evaluation. 

Standards and Tests. — Identification. — A 
bluish green to dark green color is produced on 
adding 1 drop of a 1 in 100 solution of sodium 
nitrite to a mixture of 5 mg. of bacitracin and 
5 ml. of />-dimethylaminobenzaldehyde T.S. Loss 



on drying. — Not more than 5 per cent, when dried 
in vacuum at 60° for 3 hours. pH .— The pH of 
a solution containing 10,000 Units of bacitracin 
per ml. is between 5.5 and 7.5. Pyrogen. — Bacit- 
racin, used in a test dose of 1 ml. per Kg. of a 
solution containing 300 units per ml., meets the 
requirements of the test. Safety. — Bacitracin, used 
in a test dose of 0.5 ml. of a solution in saline 
T.S. containing 200 units per ml., given intra- 
muscularly, meets the requirements of the test. 
Sterility. — Bacitracin is required to be free of 
bacteria, molds and yeasts. Content variation. — 
The content of bacitracin in containers intended 
for use with water vehicles for parenteral adminis- 
tration is not less than 85 per cent of the labeled 
unitage. U.S. P. 

Assay. — Bacitracin is assayed by the official 
microbial assay. U.S.P. For important contribu- 
tions on the assay of bacitracin see Johnson et al. 
(Science, 1945, 102, 376); Darker et al. (J. A. 
Ph. A., 1948, 37, 156; Pinzelik et al., Appl. 
Microbiol., 1953. 1, 293). 

Unit. — The U.S.P. Unit of Bacitracin is de- 
fined as the bacitracin activity exhibited by 23.8 
micrograms of the dried master standard of the 
federal Food and Drug Administration. 

Uses. — When bacitracin first became available 
from submerged fermentation it was a relatively 
crude drug that caused a variety of untoward 
effects when injected. Most important of these 
was renal damage with tubular necrosis followed 
by various sequelae. Therefore, use of the anti- 
biotic generally was limited to topical application 
or, for intestinal amebiasis, to the oral route. The 
latter treatment can be used safely because 
bacitracin is not absorbed from the gastrointes- 
tinal tract. 

Following intramuscular injection of bacitracin, 
however, the drug is absorbed and relatively large 
amounts occur in the blood and are excreted in 
the urine at a rate corresponding to the rate of 
glomerular filtration (Eagle et al., J. Clin. Inv., 
1947. 26, 919). In humans, blood levels may 
reach 2 to 4 micrograms per ml. 1 to 2 hours after 
a single injection of 1.5 mg. of bacitracin having 
an activity of 0.03 unit per microgram. Concen- 
trations in the blood remain above 0.5 microgram 
for 5 to 6 hours (Eagle et al., loc. cit.). There- 
fore, since antibacterially effective blood levels 
can be attained and since bacitracin often is active 
against gram-positive organisms resistant to peni- 
cillin, efforts were made almost from the start to 
render the drug suitable for parenteral use by 
removing the nephrotoxic factors. 

Meleney (/. Michigan Med. Soc, 1949, 48, 
1154) reported that 87 per cent of a series of 
more than 200 patients with localized surgical 
infections responded favorably to injection of 
bacitracin solutions and he and others recom- 
mended parenteral administration on the basis of 
results with 270 patients (Surg. Gyn. Obst., 1949, 
89, 657). Seven of the patients in the series re- 
ceived the drug prophylactically. The others were 
treated for acute osteomyelitis, carbuncles, gan- 
grene, infected wounds, staphylococcal meningitis, 
etc. Ninety-six of the patients had had prior un- 
successful treatment with one or more antibiotics; 
of this group 23 had "excellent response" and 32 



Part I 



Bacitracin 



133 



"responded well" for a cure rate of about 57 per 
cent. Of 119 patients without previous treatment, 
78.1 per cent responded favorably to bacitracin. 
In accord with the earlier study by Meleney, the 
drug was found to be especially useful in cellulitis 
or deeper surgical infections when incision was 
unwise and cultures were not obtainable. Of the 
cultures reported by this group 122 strains were 
susceptible both to penicillin and to bacitracin, 
104 resisted penicillin but were sensitive to baci- 
tracin; only 11 were resistant to bacitracin while 
being sensitive to penicillin. Bacitracin was as 
effective in mixed infections, due to different 
species of gram-positive organisms, as in infec- 
tions due to a single species, rendering it espe- 
cially efficacious in chronic conditions in which 
the organisms had become penicillin-resistant. 

Despite several successful parenteral trials, 
many clinicians considered the risk of nephro- 
toxicity to outweigh the benefits to be gained 
from parenteral use of bacitracin (especially since 
other effective antibiotics were available), and as 
recently as 1953 the N.N.R. stressed that "it 
[bacitracin] must never be administered intra- 
muscularly or intravenously." 

As methods of purification have been improved, 
however, some of the nephrotoxic constituents 
have been eliminated and reports of successful 
parenteral applications of the drug with no un- 
toward effects are becoming more common, espe- 
cially when fluid intake is increased to at least 
2^2 liters per day. Intramuscular injection of 
bacitracin (10,000 to 20,000 units every six hours 
until fever subsides) may afford satisfactory treat- 
ment for infections caused by strains of gram- 
positive organisms or of meningococci refractory 
to penicillin (Teng, Arch. Neurol. Psychiat., 1950, 
64, 861; Meleney et al, Surg. Gyn. Obst., 1952, 
94, 401). The usual intramuscular dose is 10,000 
to 20,000 units every 6 to 8 hours until fever 
subsides. Since approximately two-thirds of pa- 
tients with pneumococcal pneumonia respond to 
bacitracin, it is useful if the clinical course is not 
affected by penicillin. The drug enters the pleural 
fluid readily. More recently Meleney and Johnson 
{Antibiotics Annual, 1953-1954, p. 251) reported 
on an additional 60 cases, half of whom were 
given parenteral bacitracin prophylactically and 
half for established infections. Bacitracin from 
four different producers was used. A wide variety 
of clinical entities, mostly surgical, was included. 
Some cases were treated for periods up to 98 days 
with only slight evidence of nephrotoxicity. Cases 
showing kidney injury before treatment showed 
no greater damage during treatment than did 
those with normal kidney function, suggesting 
that changes induced by bacitracin are not the 
same as those occurring as the result of disease 
or the degenerative changes of old age. In 75 per 
cent of the patients there were slight signs of 
nephrotoxicity; in only 2 of the 60 patients was 
the toxicity disturbing. 

Bacitracin may be administered intrathecally, 
intracranially, or by subarachnoid injection for 
meningococcal or pneumococcal meningitis two 
to three times daily for periods up to two weeks 
without causing any renal disturbance (Teng, 
1950, loc. cit.). However, single intraspinal doses 



should not exceed 1000 units in children under 
2 years of age or 10,000 units in adults. 

Teng et al. {Surgery, 1953, 33, 321) reported 
on bacitracin treatment of 61 patients with intra- 
cranial and cranial suppuration. The drug was 
applied locally by dusting on exposed brain tis- 
sue during surgery and also was injected intra- 
thecally, intracerebrally, or intraventricularly. 
Whether or not supportive intramuscular injec- 
tion was used, the drug was uniformly successful 
and there were no untoward effects. The authors 
concluded that bacitracin is the antibiotic of 
choice for neurologic infections. The same authors 
later compared bacitracin with penicillin, strepto- 
mycin, polymyxin B, and neomycin {Antibiotics 
Annual, 1953-1954, p. 249). Bacitracin was the 
least irritating and least toxic to components of 
the central nervous system. 

Topical Applications. — Despite the numerous 
reports of successful systemic use of bacitracin, 
its major therapeutic application is still in topical 
or local medication as an adjunct to therapy with 
other antibiotics. Eggers {Am. J. Ophth., 1951, 
34, 1706) treated more than 400 cases of ocular 
infections (conjunctivitis, blepharitis, dacryo- 
cystitis, corneal ulceration, etc.) with bacitracin 
ophthalmic solution (1000 units per ml.) by in- 
stilling a few drops into the eye every l /i to 1 
hour during the day. Patients generally were suffi- 
ciently improved after treatment for 2 days to re- 
turn to work. The drug was used prophylactically 
with equal success following ocular surgery. 

In dermatology, ointments containing 500 units 
of bacitracin per Gm. of suitable base are ex- 
tremely efficacious in eradicating many pyogenic 
skin infections (Miller et al., Arch. Dermat. 
Syph., 1949, 60, 106). Bacitracin is considered 
especially useful in dermatology because of the 
low incidence of local reactions to it and the rela- 
tively high incidence of sensitization following 
local application of penicillin or of sulfonamides 
to the skin. Derzavis {J.A.M.A., 1949, 141, 191) 
patch-tested 150 adults with a bacitracin ointment 
for 48 hours; all were negative. A second appli- 
cation in the same areas in 50 of the subjects two 
weeks later revealed no allergenicity. 

Only a small fraction of bacitracin is released 
from grease bases, but practically all is available 
from water-miscible bases. Bacitracin is readily 
released from a base with the following composi- 
tion and remains stable in it for at least two 
weeks: cetyl alcohol, 10 Gm. ; glycerin, 10 Gm.; 
sodium lauryl sulfate, 1 Gm.; distilled water, 
74 ml. 

Conditions treated successfully with bacitracin 
formulated in the above ointment (Miller et al., 
loc. cit.) included impetigo (18 patients), fol- 
liculitis (16 patients), infectious eczematoid der- 
matitis (13 patients), vesiculopustular eruption 
(10 patients) and ecthyma (5 patients). Derzavis 
et al. reported similar satisfactory results in 
138 patients with pyoderma of various origins 
{J.A.M.A., 1949, 141, 191). Practical use of 
bacitracin ointments in many types of skin in- 
fections has been reviewed by Finnerty {New 
Eng. J. Med., 1951, 245, 14) and by Wrong et al. 
{Can. Med. Assoc. J., 1951, 64, 395). 

In experimental dermatologic studies, mixtures 



134 



Bacitracin 



Part I 



of bacitracin with streptomycin and polymyxin 
have proved useful in prophylaxis of skin infec- 
tions with common bacteria and in the treatment 
of chronic tropical ulcers due to bacteria and 
treponemas (Loughlin et al., Antibiotics Annual, 
1953-1954, p. 291). A lotion containing 500 units 
of bacitracin and 10,000 units of polymyxin B 
sulfate in each ml. has proved effective in super- 
ficial skin infections caused by or secondarily in- 
vaded by staphylococci or streptococci and in 
sterilizing leg ulcers and in making possible sur- 
gical closure of the ulcers (Philip, Antibiot. 
Chemother., 1954, 4, 763). A suitable lotion can 
be formulated with Carbowax, Veegum, sorbitol, 
and lecithin. Such a bacitracin-polymyxin lotion 
cannot be considered a dermatologic cure-all; but 
it is highly efficacious in exudative skin diseases 
where the lesions are invaded by pus-producing 
bacteria and where there are avenues permitting 
exudates to reach the surface of the skin and the 
lotion to penetrate beneath the surface. 

Formulated with vasoconstrictors or with other 
antibiotics, or alone, bacitracin may be adminis- 
tered as an aerosol or in nasal drops for treating 
susceptible bacterial sino-respiratory infections. 
Prigal and Furman (Am. Coll. Allergists Meet., 
1949) found among 100 patients with infections 
of sinuses and respirator}' tract that 13 of 17 
cases treated with bacitracin aerosol were mark- 
edly improved and that similar results were 
achieved with 12 of the remaining 83 patients 
treated with bacitracin-penicillin aerosol. 

A paste containing penicillin, streptomycin, 
and bacitracin was used by Grossman (/. A. 
Dent. A., 1951, 43, 265) to sterilize root canals 
in pulpless teeth. Bacitracin-polymyxin mixtures 
gave excellent results in a series of 89 cases of 
otitis externa reported bv Graves {Eye, Ear, Nose 
& Throat Monthly, 1952, 31, 32). 

Vaginal suppositories containing bacitracin pro- 
vide effective prophylaxis against contamination 
by gram-positive organisms in hysterectomies 
(Turner et al., Am. J. Surg., 1951, 82, 498). 

Toxicology. — Bacitracin is virtually nontoxic 
when administered locally as an ointment, solu- 
tion, or aerosol or when injected intrathecally, 
intra cranially, or intracerebrally. Intramuscular 
injection, however, may be followed by the symp- 
toms of nephrotoxicity mentioned above. Other 
toxic effects from systemic administration occur 
with varying frequency; these include local pain, 
anorexia and nausea, urinary frequency, and 
nocturia. Generally, the kidney damage from 
bacitracin is completely reversible, but prudence 
indicates withdrawal of the drug when symptoms 
of toxicity begin to appear. 

Bacitracins A and F have about the same 
nephrotoxicity on a weight basis. But, as Coding- 
ton (loc. cit.) has pointed out, "since F has no 
potency against the test organism, an equal num- 
ber of units of material containing a large propor- 
tion of F would . . . produce a greater toxic effect 
than material containing a small amount of F." 
Differences in proportions of bacitracins A and F 
probably account in part for the varying potency 
of different fermentation batches of bacitracin. 

Summary. — Bacitracin is a water-soluble poly- 
peptide antibiotic that is elaborated by the Tracy I 



strain of Bacillus licheniformis (or subtilis). The 
drug is stable when dry but deteriorates when in 
solution. Its antimicrobial activity is not affected 
by serum, pus, or tissue debris. 

Bacitracin closely resembles penicillin in the 
range of its antimicrobial spectrum; it is active 
against most cocci, whether aerobic or anaerobic; 
against gram-positive rods; and several spiro- 
chetes. It is not effective, in clinically practicable 
doses, against gram-negative organisms but it is 
Rot destroyed by them, as penicillin sometimes is, 
and therefore can be used therapeutically for con- 
trol of gram-positive pathogens in certain mixed 
infections in which penicillin would be ineffective. 
Among gram-positive organisms and cocci, fewer 
strains are resistant to bacitracin than to peni- 
cillin, possibly because the former antibiotic has 
not been so badly abused by indiscriminate use. 

Bacitracin has been used topically or locally 
with eminent success in pyogenic skin infections, 
ocular infections, sterilization of root canals in 
pulpless teeth, and in treating oral lesions, espe- 
cially those due to spirochetes. 

In surgery, bacitracin has been used prophy- 
lactically and therapeutically to control both sys- 
temic and local infection, and in neurosurgery it 
may prove to be the antibiotic of choice. It can 
be applied directly to brain tissue without produc- 
ing untoward effects. Intrathecal, intracranial, 
and intracerebral injections are effective in con- 
trolling meningococcal infections. 

Intramuscular and intravenous injections of 
solutions of bacitracin in saline or water are be- 
coming safer as improved purification procedures 
remove more of the nephrotoxic constituents. 
However, it appears that not all the nephro- 
toxicity can be ascribed to impurities; some of 
the constituents of bacitracin itself are damaging 
to the tubules. Consequently, parenteral adminis- 
tration should be attempted only in a hospital 
where there are proper facilities and then only 
by personnel competent to recognize proteinuria 
and other early symptoms of toxicity. Daily 
urinalysis and frequent blood urea-nitrogen de- 
terminations should be made. If fluid intake is 
raised to at least 2500 ml. daily in adults (pro- 
portionately in children) there is little risk of 
nephrotoxicity. H 

Dosage. — For external use the official oint- 
ment, containing 500 units of bacitracin per Gm., 
is applied topically as required one or more times 
daily; the concentration range in ointments is 250 
to 1000 units per Gm. Solutions containing 250 
to 1000 units per ml. have also been used 
externally. 

When administered orally, in treating intestinal 
amebiasis, 20,000 to 30,000 units is given every 
6 hours, after meals and at bedtime. 

For intramuscular administration, in certain 
circumstances (v.s.), a reasonable average daily 
dose for an adult is 50,000 units given in equal 
divided doses six to eight hours apart until fever 
subsides. The safe range for a single dose is 
10,000 to 20,000 units. The higher dose may be 
increased slightly, but the total daily dose should 
not exceed 100,000 units. For children the dose 
should be reduced in proportion to weight. Usu- 
ally a safe basis for calculation of doses for chil- 



Part I 



Barbital 



135 



dren or adults is 100 to 200 units per Kg. per 
single dose. Meleney and Johnson (1953, loc. 
cit.) recommended that (1) the concentration of 
bacitracin in the injection should never exceed 
10,000 units per ml. of sterile isotonic sodium 
chloride solution for injection containing 1.5 per 
cent monocaine hydrochloride or 2 per cent pro- 
caine hydrochloride, (2) the total daily dose for 
adults should never exceed 100,000 units nor 
should a single dose exceed 25,000 units (pro- 
portionately less for children), (3) fluids should 
be forced to at least 2500 ml. daily for adults, 
and (4) intake and urinary output should be 
measured accurately every day. The daily output 
should be about 1 liter; if it falls below 600 ml. 
on a 2500 ml. intake, the drug should be discon- 
tinued except in rare cases. 

For intrathecal, intracisternal, etc., injection 
a concentration of 1000 units per ml. of sterile 
isotonic sodium chloride solution for injection is 
used in a total daily dose of 10,000 units for a 
patient over 15 years of age; for infants and 
young children, the total daily dose varies from 
250 to 5000 units according to size, site of injec- 
tion and severity of the infection. Procaine 
should not be used in this area. 

For intraperitoneal injection in the prophylaxis 
or treatment of peritonitis, 20,000 units in 20 ml. 
of sterile isotonic sodium chloride solution for in- 
jection is instilled or sprayed over the operative 
site. 

Storage. — Preserve "in tight containers, and 
keep in a cool place." U.S.P. 

BACITRACIN OINTMENT. U.S.P. 

"Bacitracin Ointment is bacitracin in an anhy- 
drous petrolatum base. Its potency is not less 
than 85 per cent of the labeled potency. The 
labeled potency is not less than 500 U.S.P. Units 
per Gm. Bacitracin Ointment conforms to the 
regulations of the federal Food and Drug Admin- 
istration concerning certification of antibiotic 
drugs.'; U.S.P. 

Bacitracin ointment may be prepared by levi- 
gating 500,000 U.S.P. Units of bacitracin with 
65 Gm. of liquid petrolatum, and then incorporat- 
ing the mixture with 925 Gm. of white petro- 
latum. If a firmer preparation is desired up to 
40 Gm. of liquid petrolatum may be replaced by 
an equal amount of white petrolatum. U.S.P. 

Bacitracin ointment contains not more than 1 
per cent of water, when determined by the Karl 
Fischer method. 

For uses of this ointment see the preceding 
monograph. 

Storage. — Preserve "in collapsible tubes, pref- 
erably in a cool place." U.S.P. 

ADHESIVE ABSORBENT BANDAGE. 
U.S.P. 

Adhesive Absorbent Compress, Adhesive Absorbent 

Gauze, Adhesive Bandage, [Carbasus Absorbens 

Adhaesiva] 

Sp. Gasa Absorbente Adhesiva. 

Description. — "Adhesive Absorbent Bandage 
is a sterile individual dressing prepared by affixing 
a plain absorbent compress to a strip of film or 



fabric coated with a pressure-sensitive adhesive 
composition. One or more colors or bacteriostatic 
agents or both, if nontoxic and harmless in the 
concentration employed, may be added to the 
compress. The weight of the compress is not less 
than that of a compress of the same area com- 
posed of four layers of Type I Absorbent Gauze. 
The compress is substantially free from loose 
threads or ravelings. The adhesive strip may be 
perforated over the compress, and the back may 
be coated with a water-repellent film. The ad- 
hesive surface is protected by overlapping strips 
of crinoline or other protective material of a 
width not less than that of the dressing. Sterility. 
— Adhesive Absorbent Bandage meets the re- 
quirements of the Sterility Tests for Solids." 
U.S.P. 

Adhesive absorbent bandage is the official title 
for the convenient dressings available on the 
market under various trade-marked names, such 
as band-aids and quick-aids. Such bandages, which 
sometimes contain bacteriostatic agents, are use- 
ful for dressing minor wounds. 

Storage and Labeling. — "Each Adhesive 
Absorbent Bandage not exceeding 15 cm. (6 
inches) in width is packaged individually in such 
manner that sterility is maintained until the indi- 
vidual package is opened. One or more individ- 
ual packages are packed in a second protective 
container. The label of the second protective con- 
tainer bears a statement that the sterility of the 
Adhesive Absorbent Bandage cannot be guaran- 
teed if the individual package has been damaged 
or previously opened. If the compress is colored 
with a dye which is not claimed to be a bacterio- 
static agent, the label shall bear a statement that 
the compress is colored, but the coloring agent 
does not render the Bandage antiseptic. If the 
compress contains one or more bacteriostatic 
agents, the label shall bear the name of each such 
agent. Each container indicates the name of the 
manufacturer, packer or distributor, and each 
protective container indicates also the address 
of the manufacturer, packer or distributor." U.S.P. 

BARBITAL. N.F. (B.P.), LP. 

Diethylbarbituric Acid, BarSitone, Diethylmalonylurea, 
[Barbitalum] 




The B.P. defines Barbitone as 5:5-diethylbarbi- 
turic acid and indicates that it may be obtained 
by condensing ethyl diethylmalonate with urea. 

B.P. Barbitone; Barbitonum. Veronal (W'inthrop) . 
Acidum diaethylbarbituricum. Fr. Diethylmalonyluree. 
Ger. Diathylbarbitursaure ; Diathylmalonylharnstoff. It. 
Acido dietilbarbiturico. Sp. Acido dietilbarbiturico; 
Barbital. 

Barbital, prepared by Conrad and Guthzeit in 
1882 but not used in medicine until 1904, was the 
first of the now extensive series of synthetic 
hypnotic drugs derived from barbituric acid (so 
named by Baeyer, in 1863, in honor of a friend, 



136 



Barbital 



Part I 



Fraulein Barbara). It is that derivative of bar- 
bituric acid or malonylurea (for structural for- 
mula and discussion see under Barbiturates, Part 
II) in which the two hydrogen atoms attached to 
the carbon atom in number five position have 
been replaced by two ethyl radicals. Most bar- 
biturates differ chemically only in the nature of 
the substituent groups attached to this particular 
carbon atom. 

Conrad and Guthzeit prepared barbital by the 
action of ethyl iodide on the silver derivative of 
barbituric acid. Commercially it is made by the 
condensation of diethylmalonic ester with urea in 
the presence of sodium ethoxide or metallic so- 
dium. The ester may be prepared from mono- 
chloroacetic acid by intermediate conversion to 
cyanoacetic acid and ethyl malonate, the latter 
ultimately yielding diethylmalonic ester. Many 
alternative methods of manufacturing barbital 
have been proposed and used. 

Because of enol formation, in which the 
— NH.CO.NH — group of barbital functions as 
— N:COH.NH — , it is possible to replace the 
hydrogen of the hydroxyl group by sodium 
through interaction with sodium hydroxide, form- 
ing the official barbital sodium. Other bases func- 
tion similarly. 

Description. — "Barbital occurs as colorless or 
white crystals, or as a white, crystalline powder. 
It is odorless, has a slightly bitter taste, and is 
stable in air. Its solutions are acid to litmus paper. 
One Gm. of Barbital dissolves in 130 ml. of water, 
in about 15 ml. of alcohol, in 75 ml. of chloro- 
form, and in 35 ml. of ether. One Gm. dissolves 
in about 13 ml. of boiling water. It is soluble in 
acetone and in ethvl acetate. Barbital melts be- 
tween 188° and 192°." N.F. The B.P. states that 
barbital is soluble in aqueous solutions of alkali 
hydroxides and of alkali carbonates. 

Standards and Tests. — Identification. — (1) 
Ammonia is evolved on boiling 200 mg. of bar- 
bital with 10 ml. of sodium hydroxide T.S. (2) 
About 300 mg. of barbital is shaken with 1 ml. 
of 1 N sodium hydroxide and 5 ml. of water for 
2 minutes and the mixture filtered. On adding 
mercuric nitrate T.S. to one-half of the filtrate 
a white precipitate, soluble in ammonia T.S., is 
produced; on adding silver nitrate T.S. dropwise 
to the remainder of the filtrate a white precipi- 
tate, at first redissolving, is produced with an 
excess of the precipitant. Loss on drying. — Not 
over 1 per cent, when dried at 105° for 2 hours. 
Residue on ignition. — Not over 0.1 per cent. 
Readily carbonizable substances. — A solution of 
500 mg. of barbital in 5 ml. of sulfuric acid has 
no more color than matching fluid A. Benzene 
derivatives. — No yellow color develops on shaking 
500 mg. of barbital with 5 ml. of nitric acid. U.S.P. 

The B.P. includes a test for the limit of neutral 
and basic substances; this consists in dissolving 
1 gram of barbitone in a slight excess of sodium 
hydroxide solution, extracting with ether and. 
after evaporating the solvent, weighing the resi- 
due — which should be not more than 2 mg. The 
LP. has a similar test but the limit is half that 
of the B.P. 

Incompatibilities. — Barbital is unstable in 



the presence of alkali, undergoing hydrolytic 
cleavage of the molecule to form therapeutically 
inactive products (see also Incompatibilities under 
Barbital Sodium) . 

Uses. — Action. — Barbital is a hypnotic. It de- 
presses the intellectual function and produces 
sleep. After small doses this effect merges into 
normal sleep, according to the encephalographic 
studies of Brazier and Finesinger (Arch. Neurol. 
Psychiat., 1945, 53, 51). The respirations may be 
somewhat slowed and the blood pressure reduced 
slightly. At this stage there is very little, if any, 
reduction in pain perception (Hale and Grabfield, 
/. Pharmacol., 1923, 21, 77) and, therefore, bar- 
bital does not replace the analgesics though it may 
enhance their effect. Gardner (Pennsylvania M. J., 
1944, 47, 451) cautioned against substitution of 
barbiturates for opiates for relief of pain. Indeed, 
its utility is much diminished unless attending 
pain is attended by an analgesic agent. Following 
sleep induced by barbital the patient awakens in 
a normal condition, though a sense of heaviness 
may persist for an hour or two. 

With large doses the sleep may pass into com- 
plete coma resembling surgical anesthesia, and 
there occur a variety of functional changes which 
van.' with dosage and individual susceptibility. 
Respiration is steadily depressed. The effect on 
general metabolism is not much greater than 
would be expected from the pronounced muscular 
relaxation. Gruber (/. Pharmacol., 1936, 56, 432) 
demonstrated that barbital and many of its de- 
rivatives directly depress intestinal musculature. 
Porter and Allamon (/. Pharmacol., 1936, 58, 
178) found that it lowers the threshold of reflex 
excitability in the spinal cord, which may explain 
its beneficial effect in certain convulsive disorders. 
For a review of the general physiologic action of 
barbital see Wagner (J.A.M.A., 1933, 101, 1787) 
and Tatum (Physiol. Rev., 1939, 19, 472). 

In addition to its use as a hypnotic barbital has 
been used in small doses in anxiety states, sea- 
sickness, and similar conditions. It is decidedly 
inferior to phenobarbital in treatment of the con- 
vulsive state, lacking the specific corticomotor 
depressant action of the latter drug. It has been 
used prior to local applications of cocaine to pre- 
vent reactions. H 

Metabolism. — The major portion of barbital 
is excreted unchanged through the kidneys ; elimi- 
nation may require several days even in normal 
animals. Argy et al. (J. Pharmacol., 1936, 57, 
258) reported that rapidity of excretion provided 
an accurate index of kidney function; in renal 
disease elimination is as slow as 3.2 per cent in 
24 hours. Qualitative and quantitative methods 
of determining barbital were reported by Kozelka 
and Tatum (/. Pharmacol., 1937, 59, 54). Masson 
and Bleland (Anesth., 1945, 6, 483), reporting on 
the inactivation and ehmination of 29 different 
barbiturates in partially hepatectomLzed or com- 
pletely nephrectomized rats, suggested that they 
be classified into four groups, depending on the 
site of detoxication : (1) those detoxified by the 
kidney, including barbital and phenobarbital: 
(2) those detoxified by the liver, including amo- 
barbital, aprobarbital, hexethal, hexobarbital, 



Part I 



Barbital 



137 



pentobarbital sodium, probarbital, propallylonal, 
and secobarbital; (3) those detoxified by both 
liver and kidney, including butethal, cyclobarbital, 
diallylbarbituric acid, and vinbarbital; (4) those 
detoxified by all body tissues, including thiopental 
and other thiobarbiturates. 

Toxicology. — Although barbital is a useful 
drug, it is capable of doing harm when improperly 
employed. The conference on distribution of bar- 
biturates held by the Committee on Legislation 
of the American Pharmaceutical Association 
(J.A.M.A., 1945, 129, 1264) recommended uni- 
form state laws to govern its dispensing. Curran 
(/. Nerv. Ment. Dis., 1944, 100, 142) called at- 
tention to the fact that from 0.3 to 1 per cent of 
all psychiatric admissions to hospitals in the 
United States are attributable to use of drugs. 

Habituation. — Brownstein and Pacella {Psych. 
Quart., 1943, 17, 112) noted that convulsive 
seizures may ensue from sudden withdrawal of 
barbiturates in individuals who manifest no such 
tendency clinically or by electroencephalographic 
examination. Green and Koppanyi (Anesth., 1944, 
5, 329) demonstrated that dogs develop cross- 
tolerance for various barbiturates after receiving 
one of them; they believe this to be a true cellu- 
lar tolerance, though of brief duration. Psychic 
dependence rather than true addiction, as in the 
case of morphine, is more common. Seevers and 
Tatum (7. Pharmacol., 1931, 42, 217) showed 
that prolonged use of barbital in animals may 
cause pathological alteration of the cerebral struc- 
ture. Robinson (/. Missouri M. A., 1937, 34, 
374) believed that analogous changes may occur 
in human addition. Work (Arch. Neurol. Psychiat., 
1928, 19, 324; pointed out that habitual use may 
lead to paranoid states. In individuals with per- 
sonality abnormalities, Isbell and White (Am. J. 
Med., 1953, 14, 558) described barbiturate addic- 
tion often associated with abuse of both alcohol 
and amphetamine and rarely with opiates. These 
cases consumed more than 800 mg. of one of the 
potent and moderate-duration barbiturates such 
as pentobarbital, amobarbital, etc., by mouth 
daily. Injection of the contents of a capsule causes 
severe irritation. Although some tolerance exists, 
an increase of only 100 mg. above the individual's 
usual daily dose causes acute barbiturate poison- 
ing. A definite abstinence syndrome is described 
in such individuals (Isbell et al., Arch. Neurol. 
Psychiat., 1950, 64, 1). During the first few hours 
after discontinuing the drug, the sedative effects 
of the barbiturate diminish but within 8 to 16 
hours anxiety, nervousness, headache, twitching 
of muscle groups, tremor, weakness and impaired 
circulatory responses to changes in body posture 
and other stimuli appear. There is progressive 
slowing of the abnormally rapid electroencephalo- 
graph pattern in these cases and then bursts of 
spike and dome complexes appear; a convulsive 
seizure of grand mal type often occurs within 16 
to 48 hours after the last dose of barbiturate. 
Confusion follows the convulsion and in some 
cases progresses into a delirium resembling de- 
lirium tremens of alcoholism; severe exhaustion 
may develop. Fraser et al. (Ann. Int. Med., 1953, 
38, 1319) reported a death. Usually after several 



days the agitation subsides, the patient sleeps and 
recovers. 

Suicide. — In recent years poisoning by barbital 
and allied substances has become very frequent. 
While many cases occur as the result of unex- 
pected sensitiveness to the drug or injudicious 
dosage for therapeutic purposes, the majority of 
the serious cases have been suicidal. In fact, in 
1936 more than 300 suicides in the United States 
were produced by barbiturates (Hambourger, 
J. A.M. A., 1939, 112, 1340). The popularity of 
barbiturates for suicidal use continues despite 
increasing restrictions on their sale. 

Symptoms. — The chief symptom of acute poi- 
soning is stupor, merging into deep coma which 
may persist for days. The respiration is slowed, 
in some cases markedly so, and accompanied by 
cyanosis and even by Cheyne-Stokes breathing. 
The anoxemia leads to a fall in blood pressure as 
a result of capillary dilatation. The body tem- 
perature may be increased, but if shock ensues 
the skin becomes cold and moist, and the pulse 
weak and rapid. Lowered blood pressure together 
with the antidiuretic action of barbital may lead 
to urinary suppression. The urine may contain 
hematoporphyrin. The pupils may be either 
dilated or contracted. The deep tendon reflexes 
are not altogether absent until coma is profound. 
Death may occur in a few hours from acute 
respiratory failure or later from pulmonary edema 
or hypostatic pneumonia. According to Quastel 
and Wheatley (Proc. Roy. Soc. Med., 1932, B 
112, 60), barbiturates inhibit oxidation of glucose, 
lactate, and pyruvate, though not of succinate, 
within brain tissue. 

The fatal doses reported for barbital have 
ranged from 2 Gm. (30 grains) to as high as 16 
Gm. (240 grains), according to Hambourger 
(J.A.M.A., 1940, 114, 2015). The effects of bar- 
biturate intoxication have been summarized by 
Billow (/. Lab. Clin. Med., 1944, 27, 265) as 
follows : 





Dose in Gm. 






Producing 






Severe Intoxi- 






cation with 


Fatal Dose 




Recovery 


in Gm. 


Allonal 


10 


More than 15 


Amobarbital 


1.5 to 2 


2 to 3 


Barbital 


3 to 10 


5 to 20 


Butallylonal 


0.5 to 1 


More than 1 


Diallylbarbituric 






Acid 


2 to 2.5 


More than 2.5 


Pentobarbital So- 






dium 


More than 1 


More than 2 


Phanodorn 


1.2 


More than 10 


Phenobarbital 


4 to 7 


6 to 9 



Differential diagnosis from poisoning by other 
aliphatic narcotics is almost impossible without 
the history or chemical examination. The absence 
of odor on the breath distinguishes it from alcohol 
or paraldehyde narcosis, but it must be remem- 
bered that in many instances patients are under 
the influence of alcohol when they take barbital. 

In chronic poisoning with barbital the mental 



138 



Barbital 



Part I 



features resemble paresis (Curran. /. Nerv. Ment. 
Dis., 1944, 100, 142; Isbell and White, loc. cit.), 
there being silly euphoria and disorientation even 
to the point of hypomania, despite drowsiness. 
There is impaired mentation, loss of emotional 
control, poor judgment, confusion and rarely a 
toxic psychosis. Nystagmus, dysarthria, ataxia, 
adiadokokinesis and an abnormally fast electro- 
encephalogram pattern is found. Respiration and 
nutrition are usually normal. Bromide intoxica- 
tion, on the other hand, presents a delirium with 
hallucinations, confabulation, and vestibular phe- 
nomena; there may be nystagmus, convulsive 
movements, a positive Babinski reflex, intention 
type tremors, a positive Romberg sign with cere- 
bellar dysfunction and unsteady gait in association 
with vestibular derangement. 

Idiosyncrasy to barbiturates may be acquired, 
especially in individuals otherwise allergic; doses 
as low as 300 mg. (5 grains) may cause fever, 
scarlatiniform eruptions with desquamation or 
angioneurotic edema. 

Treatment of Acute Poisoning. — In view of the 
extensively disordered physiology of the organism 
produced by barbiturate poisoning active therapy 
is of paramount importance. In addition to these 
symptomatic measures two basic considerations 
should guide the treatment of profound barbital 
intoxication: (1) the compound is poorly excreted 
or metabolized; thus it may be necessary to 
watch the patient carefully for several days fol- 
lowing withdrawal of the drug in order to main- 
tain adequate cardiovasculorespiratory function. 
(2) Because of the depressed respiratory excur- 
sions over many hours, adequate chemothera- 
peutic prophylaxis against the development of 
pneumonia is a justifiable precaution until the 
patient is out of clanger. Burdick and Rovenstine 
(Ann. Int. Med., 1945. 22, 819) and Dorsey 
(/. Nerv. Ment. Dis., 1944, 99, 367) recommend 
early and adequate symptomatic use of picrotoxin. 
Dorsey recommended the following plan of 
treatment: On establishing diagnosis the patient's 
head is lowered, external heat is applied, an air- 
way maintained, and gastric lavage performed 
with a quart of warm water each of three times. 
Sixty grams of magnesium sulfate solution are 
instilled to hasten bowel elimination. Continuous 
intravenous administration of 5 per cent dextrose 
in normal saline is begun. Through the tubing a 
picrotoxin solution containing 3 mg. per ml. is 
injected at the rate of 1 ml. per minute until it 
produces tremors and twitching of the eyes or 
lips, at which level the maximum beneficial effect 
on cardiac and respiratory centers obtains. A 1-ml. 
dose must be repeated about every 5 minutes to 
maintain this effect. The patient becomes restless 
as improvement begins, and the frequency of in- 
jections may be reduced to each 10 or 15 minutes. 
Picrotoxin administration is discontinued when 
the patient moves about the bed. Since picrotoxin 
disappears in 30 minutes, its use must be continued 
for an adequate time, the usual total requirement 
being about 300 mg. Amphetamine sulfate (q.v.) 
or pentylenetetrazol (q.v.) are also used. Ad- 
juncts to this specific stimulation include injec- 
tion of 500 mg. (~y 2 grains) of caffeine and 
'sodium benzoate intravenously each hour, the 



inhalation of a mixture of 5 per cent carbon 
dioxide and 95 per cent oxygen, or artificial res- 
piration as necessary, and the administration of 
plasma or blood transfusion for shock. The pa- 
tient's position is changed hourly and the bladder 
is catheterized every 6 hours. 

Soskin and Taubenhaus (/. Pharmacol., 1943, 
78, 49) used a 10 per cent aqueous succinate 
solution intravenously with success in a patient 
who failed to respond after 3 days of treatment 
with picrotoxin. so maintaining brain metabolism 
until the barbiturates were destroyed and elimi- 
nated. This use of sodium succinate could not be 
substantiated bv others (/. Pharmacol., 1944, 81, 
202; 1949, 96, 315). 

Dose. — The dose of barbital is from 300 to 
600 mg. (approximately 5 to 10 grains), one to 
two hours before bedtime. 

Barbital Elixir, X.F. IX, is prepared by dis- 
solving 35 Gm. of barbital in a mixture of 335 ml. 
of alcohol, 30 ml. of compound vanillin spirit, and 
600 ml. of glycerin, then adding 20 Gm. of cara- 
mel and enough glycerin to make 1000 ml. of 
product. The average dose of 4 ml. (approxi- 
mately 1 fluidrachm) contains about 140 mg. 
(approximately 2}i grains) of barbital. 

Storage. — Preserve "in well-closed contain- 
ers." Nf. 

BARBITAL TABLETS. 
N.F. (B.P.) (I.P.) 

Tabellae Barbitali 

"Barbital Tablets contain not less than 94 per 
cent and not more than 106 per cent of the labeled 
amount of CSH12X2O3." NJ 7 . The corresponding 
B.P. limits are 95.0 and 105.0 per cent, while 
those of the I.P. are 94.0 and 106.0 per cent. 

B.P. Tablets of Barbitone; Tabellae Barbitoni. I.P. 
Tablets of Barbital; Compressi Barbitali. Sp. Tobletas 
de Barbital. 

Assay. — A representative sample of powdered 
tablets, equivalent to about 300 mg. of barbital, 
is treated with an alkaline sodium chloride solu- 
tion to dissolve barbital and this solution is ex- 
tracted with ether to remove lubricants other than 
stearic acid or stearates. The aqueous solution is 
then acidified to liberate barbital, which is ex- 
tracted with chloroform ; the chloroform solutions 
are washed with acidified water, filtered, and the 
chloroform evaporated. The residue of barbital is 
dried at 105° for 2 hours and weighed. If stearic 
acid or a stearate has been used as a lubricant for 
the tablets the residue will contain stearic acid. 
To remove this the residue is dissolved in alcohol, 
and barium hydroxide is added to precipitate 
barium stearate while dissolving the barbital. The 
mixture is filtered, the filtrate is acidified, and 
the precipitated barbital is extracted with chloro- 
form as before, and finally weighed. X.F. The I.P. 
uses the same assay, with minor variations. In the 
B.P. assay a portion of powdered tablets repre- 
senting about 300 mg. of barbital is extracted with 
ether in a continuous extraction apparatus: the 
ether is evaporated and the residue of barbital is 
dried to constant weight at 105°. 

Usual Size. — 5 grains (approximately 300 
mg.). 



Part I 



Barium Sulfate 



139 



BARBITAL SODIUM. N.F. (B.P.) LP. 

Soluble Barbital, Barbitone Sodium, 
[Barbitalum Sodicum] 

"Barbital Sodium, dried at 105° for 3 hours, 
contains not less than 98.5 per cent of CsHn- 
N 2 Na03." N.F. The B.P. recognizes Barbitone 
Sodium as the monosodium derivative of 5:5-di- 
ethylbarbituric acid, the substance being required 
to contain not less than 98.0 per cent and not 
more than the equivalent of 101.0 per cent of 
C8HnN2Na03, calculated with reference to the 
material dried at 105°. The LP. requires not less 
than 98.0 per cent of C8HnN2Na03, no reference 
being made to drying it, or calculating to the dried 
substance. 

B.P. Barbitone Sodium; Barbitonum Sodium. LP. 
Barbitalum Natricum. Sodium Barbital; Sodium Diethyl- 
malonylurea; Sodium Diethylbarbiturate; Medinal (Scher- 
ing & Glatz); Veronal Sodium (Winthrop) . Natrium 
Diaethylbarbituricum. Ger. Diathylbarbitursaures Nat- 
rium; Veronal Natrium. It. Dietilbarbiturato di sodio. 
Sp. Barbital Sodico. 

Barbital sodium is produced by the interaction 
of barbital and sodium hydroxide, in the presence 
of water, from which solution the sodium deriva- 
tive is precipitated with alcohol. In this reaction 
the — NH.CO.NH — group of barbital is probably 
first converted to the isomeric — N:COH.NH — 
group, which subsequently reacts with sodium 
hydroxide to form — N:CONa.NH— . 

Description. — "Barbital Sodium occurs as a 
white powder. It is odorless, has a bitter taste, 
and is stable in air. Its solutions are alkaline to 
litmus paper and to phenolphthalein T.S. One Gm. 
of Barbital Sodium dissolves in about 5 ml. of 
water and in 2.5 ml. of boiling water. It is slightly 
soluble in alcohol and is insoluble in ether." N.F. 

Standards and Tests. — Identification. — (1) 
The barbital obtained in the assay melts between 
188° and 192° and responds to identification tests 
for barbital. (2) A white precipitate of barbital 
is obtained on adding diluted hydrochloric or 
sulfuric acid to a 1 in 20 solution of barbital 
sodium. (3) The residue resulting from the igni- 
tion of barbital sodium responds to tests for 
sodium. Loss on drying. — Not over 1 per cent, 
when dried for 3 hours at 105°. Heavy metals. — 
The limit is 20 parts per million. Readily carbon- 
izable substances. — A solution of 500 mg. of bar- 
bital sodium in 5 ml. of sulfuric acid has no more 
color than matching fluid A. Uncombined barbital. 
— 500 mg. of barbital sodium shaken with 20 ml. 
of absolute ether for 10 minutes yields not more 
than 3 mg. of soluble matter. N.F. The B.P. and 
the LP. limit the content of lead to 10 parts per 
million; the LP. also provides a heavy metals 
limit of 20 parts per million. 

Assay. — A sample of 500 mg. of barbital so- 
dium is dissolved in water, acidified with hydro- 
chloric acid, and the liberated barbital extracted 
with chloroform. The filtered chloroform extract 
is evaporated to dryness, the residue is dried at 
105° for 2 hours, and then weighed. The weight 
of the residue multiplied by 1.119 represents the 
weight of CsHnN2Na03. N.F. The B.P. and LP. 
assays are similar in principle, except that ether 
is employed for extracting barbital. 

Incompatibilities. — In aqueous solution, bar- 



bital sodium undergoes hydrolysis, diethylmalon- 
uric acid, diethylacetylurea and possibly further 
decomposition products being produced (see Niel- 
son, Quart. J. P., 1938, 11, 150, and Aspelund 
and Skoglund, ibid., 1938, 11, 291). The reaction 
is accelerated by an increase in temperature but 
is appreciable even at room temperature; this is 
emphasized by the fact that solutions of barbital 
sodium have been known to decompose as much 
as 50 per cent during a period of a few months, 
even when stored at room temperature. Since 
hydrolysis of barbital sodium is accompanied by 
loss of therapeutic value, aqueous solutions of 
this compound should be freshly prepared. Bar- 
bital sodium is precipitated as barbital by acids 
and acid-reacting salts. Because of its alkalinity 
it should not be prescribed along with chloral 
hydrate, which it decomposes to form chloroform 
and sodium formate, with simultaneous precipita- 
tion of barbital. 

Uses. — Because of its solubility, this drug acts 
somewhat more promptly than does barbital 
(q. v.). Being soluble in water it can be given by 
intravenous injection but has largely been replaced 
for that purpose by some of the newer sodium 
barbiturates. For discussion of uses and toxicology 
see under Barbital. S 

Dose, from 300 to 600 mg. (approximately 5 
to 10 grains). 

Storage. — Preserve "in tight containers." N.F. 

BARBITAL SODIUM TABLETS. 

N.F. (B.P.) (LP.) 

Tabellae Barbitali Sodici 

"Barbital Sodium Tablets contain not less than 
94 per cent and not more than 106 per cent of the 
labeled amount of CsHii^OsNa." N.F. The 
corresponding B.P. limits are 92.0 and 105.0 per 
cent, while those of the LP. are 94.0 and 106.0 
per cent. 

B.P. Tablets of Barbitone Sodium; Tabellae Barbitoni 
Sodii. LP. Tablets of Barbital Sodium; Compressi Bar- 
bitali Natrici. Sp. Tabletas de Barbital Sodico. 

Usual Size. — 5 grains (approximately 300 
mg.). 

BARIUM SULFATE. U.S.P. (B.P.) LP. 

[Barii Sulfas] 

BaS0 4 

"Caution. — When Barium Sulfate is prescribed, 
the title should always be written out in full to 
avoid confusion with the poisonous barium sidfide 
or sulfite." U.S.P. 

B.P. Barium Sulphate; Barii Sulphas. Blanc Fixe; Syn- 
thetic or Artificial Barytes; Artificial Heavy Spar; Snow, 
New or Permanent White. Terra Alba; Terra Ponderosa. 
Fr. Sulfate de baryum; Blanc fixe. Ger. Bariumsulfat ; 
Schwefelsaures Barium. It. Solfato di bario. Sp. Sulfato 
de bario. 

A native barium sulfate, known as barytes, 
heavy spar, barite or tiff, is the most abundant 
of the natural salts of barium and is mined ex- 
tensively in the United States. It occurs as a 
heavy, lamellar, brittle mineral, usually translu- 
cent, sometimes transparent or even opaque; 
color white or pale pink. Sometimes it occurs in 
flat rhombic prisms. 



140 



Barium Sulfate 



Part I 



The medicinal salt, however, is obtained by the 
interaction of barium hydroxide or soluble barium 
salts with sulfuric acid or soluble sulfates. Much 
barium sulfate is made, by the same reactions, for 
industrial usage; as this grade is not as pure as 
the medicinal variety it is imperative that the 
industrial grade not be used medicinally. Barium 
sulfate is often a by-product in the manufacture 
of other chemicals. 

Description. — "Barium Sulfate is a fine, 
white, odorless, tasteless, bulky powder, free from 
grittiness. Barium Sulfate is insoluble in water, 
in organic solvents, and in solutions of acids and 
of alkalies." U.S.P. 

Standards and Tests. — Identification. — (1) 
Tests for sulfate are given by barium sulfate 
when 500 mg. of it is fused with 2 Gm. each of 
anhydrous sodium carbonate and anhydrous po- 
tassium carbonate, the fused mass leached with 
hot water, and the tests performed on the filtered 
liquid. (2) Tests for barium are given by the 
well-washed residue from the preceding test after 
solution in acetic acid. Bulkiness. — 5 Gm. of 
barium sulfate, previously passed through a No. 
60 sieve, and mixed with enough water to make a 
volume of 50 ml. in a glass-stoppered graduated 
cylinder having the 50-ml. graduation about 14 
cm. from the bottom does not settle below the 
11 -ml. graduation within 15 minutes. Acidity or 
alkalinity. — 1 Gm. of barium sulfate shaken with 
20 ml. of water for 5 minutes leaves the water 
neutral to litmus paper. Sulfide. — Lead acetate 
paper is not darkened when exposed to the vapors 
of a mixture of 10 Gm. of barium sulfate, 10 ml. 
of diluted hydrochloric acid and 90 ml. of water 
boiled for 10 minutes in a 2 50-ml. Erlenmeyer 
flask. Acid-soluble substances. — Not more than 
15 mg. of residue, dried at 105° for 1 hour, is 
obtained from 50 ml. of filtrate from the insolu- 
ble residue of the preceding test (the soluble 
portion of barium sulfate is largely eliminated by 
evaporating the filtrate, dissolving it in 10 ml. of 
hot water and 2 drops of hydrochloric acid, and 
filtering). Soluble barium salts. — No turbidity 
develops within 30 minutes after the addition of 
diluted sulfuric acid to a solution of the residue 
obtained in the preceding test. Phosphate. — No 
yellow precipitate is formed on adding ammonium 
molybdate T.S. to the filtrate obtained from 1 Gm. 
of barium sulfate boiled for 5 minutes with 3 ml. 
of nitric acid and 5 ml. of water. Arsenic. — The 
limit is 1 part per million. Heavy metals. — The 
limit is 10 parts per million. U.S.P. 

The B.P. and LP. require that the loss on dry- 
ing to constant weight, at 105° and 110° re- 
spectively, not exceed 2.0 per cent. 

Uses. — Barium sulfate, by virtue of its opacity 
to x-rays and its insolubility in the fluids of the 
gastrointestinal tract, is used in medicine for 
obtaining roentgenograms of the alimentary canal. 
For this purpose it has quite generally replaced 
bismuth salts, over which barium sulfate has the 
advantages of greater opacity, lesser effect on the 
bowel, and lower cost. Barium sulfate is com- 
monly administered in aqueous suspension, the 
amount employed depending on the portion of the 
tract to be examined and the technic to be em- 
ployed. Various formulations call for from 30 to 



360 Gm., and sometimes more, of barium sulfate. 
These may be given orally or, if the examination 
is to be of the colon, by enema. 

A homogeneous suspension, free of lumps in 
order that the barium sulfate itself may have uni- 
form opacity to x-rays, is obviously desirable. In 
addition, a thin film of barium sulfate should be 
deposited on the mucosal surface and persist there 
even after most of the suspension has passed the 
area to be examined (Hodges, J. A.M. A., 1953, 
153, 1417). Ideally, it should be possible to vary 
opacity (to x-rays) and viscosity independently. 
For oral administration suspensions should pref- 
erably be flavored. Various suspending agents 
have been employed in formulating barium sulfate 
preparations, these including bentonite, kaolin 
(Haenisch, Munch, med. Wchnschr., 1911, 58, 
2375), starch (Potter, Radiology, 1953, 60, 500), 
flour, acacia, agar, gelatin (Abel, ibid., 1944, 43, 
175), lecithin, pectin, tragacanth, malted milk, 
and aluminum hydroxide gel (Swallow, Pharm. J., 
1950, 2, 434). More recently methyl cellulose 
(Marks, Am. J. Surg., 1951, 81, 6) and sodium 
carboxymethylcellulose (Bactowsky and Presto, 
Bull. Am. Soc. Hosp. Pharm., 1950, 7, 65) have 
been used; silicones and tannic acid have been 
included in certain formulations. Saccharin and 
vanillin are commonly employed for sweetening 
and flavoring suspensions to be taken orally; other 
flavoring agents, including cocoa, are also used. 
The particle size of the barium sulfate is obvi- 
ously an important factor; very minute par- 
ticles improve suspension stability and facilitate 
coating of the mucosa. Hodges alleges that the 
designation "colloidal," as applied to the suspen- 
sions, is often a misnomer. 

A barium sulfate suspension enema,, accom- 
panied by fluoroscopic observation, has been used 
therapeutically to reduce intussusception (Ravitch 
and Morgan, Ann. Surg., 1952, 135, 296). Fawcitt 
(Brit. M. J., 1943, 1, 352) recommended use of 
cotton "sandwiches" impregnated with barium 
sulfate to entangle sharp foreign bodies within the 
intestinal tract and to permit their visualization, [vj 

Toxicology. — It should be remembered that 
the soluble barium salts are actively poisonous, 
being very active stimulants to the entire bodily 
musculature. As little as 800 mg. of a soluble 
barium salt has proved fatal. The safety of barium 
sulfate in large doses is due to its insolubility. 
Karaoglanow {Pharm. Weekblad., 1918, 55, 47) 
found that from 2.5 to 4.3 milligrams of barium 
sulfate dissolve in a liter of water, according to 
the degree of fineness of the powder. The solu- 
bility is decreased by the presence of sulfate ion 
and increased by nitric or hydrochloric acid. 

Barium Sidfide. — A number of fatal cases of 
poisoning by other salts, especially the sulfide of 
barium, but including even the carbonate (Mor- 
ton, Lancet, 1945, 2, 738), which have been mis- 
takenly used for x-ray work have been recorded. 
In a case reported by Bensaude and Antoine 
{Bull. soc. med., 1919, 43, 369), the patient was 
poisoned immediately after drinking the suspen- 
sion of barium and was dead in 10 minutes. In 
other cases the appearance of symptoms has been 
delayed as much as an hour and death until the 
following day. The characteristic symptoms are: 



Part I 



Beef, Iron and Wine 



141 



burning pain in the stomach, nausea and vomit- 
ing, the latter often bilious, followed by diarrhea 
with violent abdominal cramps. The pulse is usu- 
ally slow and frequently irregular, the blood pres- 
sure being elevated. There are often vertigo and 
ringing in the ears. Death may occur suddenly 
with convulsions, or may be delayed for 10 or 12 
hours. Post-mortem examination shows intense 
congestion of the alimentary canal, with some- 
times minute hemorrhages, also congestion of the 
liver and kidney. 

The proper treatment consists in the immedi- 
ate administration of large quantities of mag- 
nesium or sodium sulfate followed by repeated 
washings of the stomach. Intravenous adminis- 
tration of calcium or magnesium salts may be 
tried to counteract the action of barium on 
muscles. Morphine and atropine are indicated for 
the pain. 

Caution. — In view of the considerable number 
of fatalities that have been recorded from the 
substitution of barium sulfide for sulfate it is 
imperative that both in writing prescriptions, and 
in labeling containers, for barium sulfate the name 
should be written out in full — never abbreviated. 

Dose. — The usual dose is 300 Gm. (approxi- 
mately 10 ounces), by mouth, in a suitable sus- 
pension (about 50 per cent w/v in water) or 360 
Gm. (approximately 12 ounces) in appropriate 
suspension as an enema. 

Storage. — Preserve "in well-closed contain- 
ers" U.S.P. 

BEEF EXTRACT. N.F. 

Extractura Carnis 

"Beef Extract is a concentrate from beef broth 
obtained by extracting fresh, sound, lean beef by 
cooking with water and evaporating the broth at a 
low temperature, usually in a vacuum, until a 
thick pasty residue is obtained." N.F. 

Fr. Extrait de boeuf. Ger. Fleischextrakt. 

Description. — "Beef Extract occurs as a yel- 
lowish brown to dark brown, slightly acid, pasty 
mass, having an agreeable meat-like odor and 
taste. Twenty-five Gm. of Beef Extract, dissolved 
in sufficient water to make 250 ml., yields a nearly 
clear solution, free from sediment." N.F. 

Standards and Tests. — Total solids. — Not 
less than 75 per cent, as determined by drying 10 
ml. of a 1 in 100 solution over sand or asbestos 
at 105° for 16 hours. Residue on ignition. — Not 
less than 30 per cent of the total solids when the 
residue from the preceding test is incinerated at 
a dull red heat. Chlorides as sodium chloride. — 
Not over 6 per cent of the total solids. Alcohol- 
insoluble solids. — Not over 10 per cent of the total 
solids. Nitrate. — No blue color develops when 
1 drop of a 1 in 10 solution of beef extract, previ- 
ously decolorized by boiling with animal charcoal, 
is added to 3 drops of a 1 in 100 solution of di- 
phenylamine in sulfuric acid. N.F. 

Assay. — For nitrogen content of alcohol-sol- 
uble substances. — An aliquot portion of the alco- 
hol filtrate remaining from the test for alcohol- 
insoluble substances, equivalent to 1 Gm. of 
alcohol-soluble solids, is digested with sulfuric 



acid, in the presence of potassium sulfate, until 
a pale yellow or nearly colorless liquid results. 
The resulting solution of ammonium sulfate is 
alkalinized with sodium hydroxide and the liber- 
ated ammonia distilled into 50 ml. of 0.1 N sul- 
furic acid; the excess acid is titrated with 0.1 N 
sodium hydroxide, using methyl red T.S. as indi- 
cator. Each ml. of 0.1 N sulfuric acid represents 
1.401 mg. of N. The amount of nitrogen thus 
found is not less than 60 mg. For nitrogen as 
ammonia. — The ammonia in 100 ml. of a 1 in 10 
solution of the extract is distilled into 50 ml. of 
0.1 TV sulfuric acid after adding 5 Gm. of barium 
carbonate to the sample; the excess of acid is 
titrated with 0.1 N sodium hydroxide using methyl 
red T.S. as indicator. Each ml. of 0.1 N sulfuric 
acid represents 1.703 mg. of NH3. The amount 
of ammonia does not exceed 0.35 per cent of the 
total solids in the solution taken. N.F. 

Uses. — Years ago beef extract was a very pop- 
ular nutritional adjunct. In large part because of 
the uncertainty of and variation in its composition 
— notwithstanding the many tests which were de- 
vised for its nutritional evaluation together with 
the development of relatively pure forms of many 
nutritional factors — the popularity of beef extract 
has waned. That it contains hydrolysis products 
of proteins and small amounts of proteins them- 
selves, together with vitamins and certain miner- 
als, is certain — but it is extremely unlikely that 
any material benefit can arise from the ingestion 
of the small amounts of extract usually taken. 
It is official as an ingredient of Beef, Iron and 
Wine. 

Storage. — Preserve "in tight, light-resistant 
containers." N.F. 

Off. Prep.— Beef, Iron and Wine, N.F. 



BEEF, IRON AND WINE. N.F 

Caro, Ferrum et Vinum 

"Beef, Iron and Wine contains, in each 100 ml., 
an amount of ferric ammonium citrate corre- 
sponding to not less than 750 mg. and not more 
than 975 mg. of Fe." N.F. 

Dissolve 30 Gm. of beef extract in 60 ml. of 
purified water with the aid of heat, cool, and add 
a mixture of 1 ml. of compound orange spirit, 
100 ml. of syrup and 50 ml. of alcohol. Dissolve 
50 Gm. of ferric ammonium citrate in 750 ml. of 
sherry wine, and add this solution to the other 
one. Add enough diluted ammonia solution to 
make the mixture neutral or slightly alkaline. 
Finally add sufficient sherry wine to make 1000 
ml. Set the solution aside for 2 days and filter. 
N.F. 

Assay. — A 10-ml. portion of beef, iron and 
wine is evaporated to dryness and the residue 
ignited until free from organic matter, finally in 
the presence of sulfuric acid. The residue of iron 
oxide is dissolved in hydrochloric acid, the solu- 
tion oxidized by means of hydrogen peroxide T.S. 
and the excess of the latter expelled by heating. 
The amount of ferric iron present is finally deter- 
mined by having it liberate iodine from potassium 
iodide, the halogen being estimated by titration 
with 0.1 N sodium thiosulfate, using starch T.S. 



142 Beef, Iron and Wine 



Part I 



as indicator. Each ml. of 0.1 N sodium thiosulfate 
represents 5.585 mg. of Fe. N.F. 

Alcohol Content. — From 17 to 25 per cent, 
by volume, of C2H5OH. N.F. 

Use. — This tonic preparation provides a thera- 
peutic dose of ferric ammonium citrate in the 
recommended average dose of 8 ml. (approxi- 
mately 2 fiuidrachms) of beef, iron and wine; 
this represents 400 mg. (approximately 6 grains) 
of ferric ammonium citrate. The presence of 
beef extract and wine may tend to stimulate the 
appetite through the flavor they give to the 
preparation. 

Storage. — Preserve "in tight, light-resistant 
containers." N.F. 

BELLADONNA LEAF. U.S.P. (B.P., LP.) 

Belladonna Herb, Deadly Nightshade Leaf, 
Belladonna; Folium 

"Belladonna Leaf consists of the dried leaf and 
flowering or fruiting top with branches of Atropa 
Belladonna Linne or of its variety Acuminata 
Royle ex Lindley (Fam. Solanacece). Belladonna 
Leaf vields not less than 0.35 per cent of the alka- 
loids 'of Belladonna Leaf." U.S.P. 

The B.P. recognizes as Belladonna Herb the 
leaves, or leaves and other aerial parts, of Atropa 
Belladonna L. and Atropa acuminata Royle ex 
Lindley (the validated name for Indian Bella- 
donna; see under Belladonna Root), collected 
when the plants are in flower and dried. An 
alkaloidal content of not less than 0.30 per cent, 
calculated as hyoscyamine, is required. The LP. 
definition and rubric are identical with those of 
the B.P. 

The B.P. recognizes also a Prepared Belladonna 
Herb (Belladonna Prceparata) and the LP. a 
Standardized Powdered Belladonna Herb (Pulvis 
BelladonncB Herbce. Standardisatus), both being 
Belladonna Herb reduced to a fine powder and 
adjusted, if necessary, to contain 0.30 per cent 
of alkaloids (limits, 0.28 to 0.32); adjustment to 
this potency may be made either by the admixture 
in suitable proportions of powdered belladonna 
herb of lower or higher alkaloidal content or by 
the addition of powdered exhausted belladonna 
herb (powdered lactose or rice starch is also per- 
mitted to be used by the LP.). This is the prep- 
aration to be dispensed when belladonna leaf or 
belladonna herb is prescribed. 

B.P., LP. Belladonna Herb; Belladonnas Herba. Bella- 
donna Leaves; Black Cherry Leaf; Dwale; Dwayberry Leaf. 
Belladonnas Folia; Herba Solani Furiosi. Fr. Belladone; 
Feuilles de belladone. Ger. Tollkirschenblatter; Bella- 
donnablatter; Tollkraut; Tollkirschenkraut. It. Foglie di 
belladonna. Sp. Hoja de belladona. 

For account of the botany and chemistry of 
this drug see Belladonna Root. 

Description. — "Unground Belladonna Leaf 
usually occurs as partly matted together, crumpled 
or broken leaves, together with some smaller 
stems and a number of flowers and fruits. The 
leaves are thin and brittle, mostly light green to 
moderate olive green. The lamina is mostly from 
5 to 25 cm. in length and from 4 to 12 cm. in 
width and possesses an ovate-lanceolate to broadly 
ovate outline, an acute to acuminate apex, an 
-entire margin, an acute to somewhat decurrent 



base and slightly hairy surface, the hairs being 
more abundant along the veins; when broken 
transversely, it shows numerous light-colored dots 
(crystal cells) visible with a lens. The petiole is 
slender and usually up to 4 cm. in length. The 
flowers possess a campanulate corolla with 5 small, 
reflexed lobes which are purplish to yellowish 
purple, becoming faded to brown or dusky yellow, 
a green, 5-lobed calyx, 5 epipetalous stamens, and 
a superior, bilocular ovary with numerous ovules. 
The fruit is subglobular, dark yellow to yellowish 
brown to dusky red or black, up to about 12 mm. 
in width and sometimes subtended by the per- 
sistent calyx and containing numerous flattened, 
somewhat reniform seeds, the latter up to about 
2 mm. in width. The stems are more or less 
flattened and hollow and finely hairy when young. 
When moistened, its odor is slight, somewhat 
tobacco-like. Its taste is somewhat bitter and 
acrid." U.S.P. For histology see U.S.P. XV. 

"Powdered Belladonna Leaf is fight olive brown 
to moderate olive green in color. The following 
are among the elements of identification: the 
separate microcrystals, the dark gray crystal cells, 
the cuticular striping of the epidermal cells, the 
vessels with ellipsoidal, bordered pits, the fibers 
of the stem, and occasional hairs and pollen grains. 
Rosette aggregates of calcium oxalate and frag- 
ments of the seed occur when the drug contains 
belladonna fruits. Examine Belladonna Leaf for 
hairs having a papillose cuticle and for raphides 
of calcium oxalate: their presence indicates adul- 
teration." U.S.P. For features distinguishing leaf 
from the two sources recognized by the pharma- 
copeias see under Belladonna Root. 

Standards and Tests. — Belladonna leaf con- 
tains not over 3 per cent of belladonna stems ex- 
ceeding 10 mm. in diameter; the acid-insoluble 
ash is not over 3 per cent. U.S.P. The B.P. allows 
not over 2.0 per cent of foreign organic matter; 
the LP. permits not more than 15.0 per cent of 
ash (total). 

Assay. — A 10-Gm. portion of leaf, in moder- 
ately coarse powder, is inserted in the thimble of 
a Soxhlet, or similar, extractor; after maceration 
with a mixture of ammonia, alcohol and ether, the 
drug is extracted with ether. Alternatively, the 
drug may be extracted in a percolator with a mix- 
ture of 3 volumes of ether and 1 volume of chloro- 
form. The extract, concentrated if necessary, is 
shaken with approximately 0.5 N sulfuric acid to 
remove alkaloids, and these are then transferred 
to chloroform after alkalinization of the aqueous 
solution. After evaporating the chloroform the 
residue of alkaloid is heated to expel non-alka- 
loidal amines, then dissolved in 15 ml. of 0.02 N 
sulfuric acid and the excess acid titrated with 
0.02 N sodium hydroxide, using methyl red T.S. 
as indicator. Each ml. of 0.02 N acid represents 
5.788 mg. of belladonna leaf alkaloids, calculated 
as hyoscyamine (or atropine). U.S.P. 

The B.P. belladonna assay is different in several 
details from the method of the U.S.P. In the B.P. 
method the drug is shaken well with a solvent 
composed of 4 volumes of ether and 1 volume of 
95 per cent alcohol for ten minutes, then dilute 
ammonium hydroxide solution is added and the 
mixture shaken frequently during one hour. This 



Part I 



Belladonna Leaf Fluidextract 143 



mixture is then transferred to a percolator, the 
drug packed firmly, and extracted, first with a 
small amount of the first solvent (4 ether and 1 
alcohol) and, finally, with ether alone until all 
the alkaloids are removed. The percolation must 
not take more than 3 hours. The percolate, which 
contains the alkaloids of the belladonna, is con- 
centrated to a small volume, mixed with chloro- 
form, and shaken out with a hydrochloric acid 
solution until the alkaloids are completely ex- 
tracted. The acidulated alkaloidal solution is 
washed with chloroform to remove chlorophyll, 
then rendered alkaline with dilute ammonia water, 
and the alkaloids again extracted with chloroform. 
The chloroform is evaporated, the alkaloidal resi- 
due dissolved in dehydrated alcohol, evaporated 
and dried at 100° until two successive weighings, 
at one hour intervals, do not differ by more than 
1 mg. This residue is dissolved in an excess of 
0.02 N sulfuric acid, and the excess of acid titrated 
with 0.02 N sodium hydroxide, using methyl red 
or cochineal as indicator. 

The LP. assay is identical with that of the B.P. 
but at the point where the alkaloids are in hydro- 
chloric acid solution, prior to alkalinization and 
extraction with chloroform, the LP. permits an 
alternative method of determining the alkaloids 
by hydrolyzing the acid solution, after it has been 
made alkaline with sodium hydroxide, so as to 
yield tropic acid (see under Atropine) ; the aque- 
ous solution is acidified, the tropic acid is ex- 
tracted with a mixture of chloroform and iso- 
propyl alcohol and, following evaporation of the 
solvent, the acid is dissolved in water and titrated 
with 0.02 N sodium hydroxide, using phenol- 
phthalein indicator. Each ml. of 0.02 N sodium 
hydroxide represents 5.788 mg. of alkaloids, calcu- 
lated as hyoscyamine. 

Uses. — For description of the physiological 
and therapeutic actions of this, see under Bella- 
donna Root, [v] 

The dose of prepared or standardized bella- 
donna leaf is from 30 to 200 mg. (approximately 
Yz to 3 grains). 

Storage. — Preserve in "well-closed contain- 
ers." U.S.P. 

BELLADONNA EXTRACT. N.F. (B.P.) 

[Extractum Belladonnas] 

"Belladonna Extract yields, from each 100 Gm., 
not less than 1.15 Gm. and not more than 1.35 
Gm. of the alkaloids of belladonna leaf." N.F. 

The B.P. Dry Extract of Belladonna contains 
1.0 per cent (limits 0.95-1.05) of the total alka- 
loids of belladonna leaf calculated as hyoscyamine. 

B.P. Dry Extract of Belladonna; Extractum Bella- 
donna Siccum. Extract of Belladonna Leaves. Fr. Extrait 
de belladone. Ger. Tollkirschenextrakt. It. Estratto idro- 
alcoolico di belladonna. Sp. Extracto de belladona. 

The N.F. recognizes this extract in two forms, 
Pilular Extract and Powdered Extract, so that 
the pharmacist may select the form best suited 
for dispensing. The pilular extract is used officially 
in the ointment. Both forms of the extract, how- 
ever, are of the same strength. The B.P. recog- 
nizes only the "dry" extract. 

Pilular Belladonna Extract. — Prepare the 



extract by percolating 1000 Gm. of belladonna 
leaf, using a menstruum of 3 volumes of alcohol 
and 1 volume of water. Macerate the drug during 
16 hours, then percolate at a moderate rate. 
Evaporate the percolate to a pilular consistence 
under reduced pressure at a temperature not over 
60°, and adjust the residue, by addition of liquid 
glucose, so that the finished extract contains 1.25 
Gm. of belladonna leaf alkaloids in 100 Gm. of 
extract. N.F. 

Powdered Belladonna Extract. — Prepare the 
extract by percolating 1000 Gm. of belladonna 
leaf, using alcohol as the menstruum. Macerate 
the drug during 16 hours, then percolate slowly. 
Evaporate the percolate to a soft extract under re- 
duced pressure at a temperature not over 60°, add 
50 Gm. of dry starch, and continue evaporation 
until a dry product results. Powder the residue 
and adjust it to contain, by the addition of suffi- 
cient starch, 1.25 Gm. of belladonna leaf alkaloids 
in 100 Gm. of extract. The extract may be de- 
prived of fat by treating either the soft extract 
first obtained, or the dry and powdered extract, as 
directed under Extracts. N.F. 

The B.P. percolates the moderately coarse 
powder of belladonna herb with 70 per cent alco- 
hol. The percolate is tested for the amount of 
alkaloids and also for the proportion of total 
solids. To the remaining percolate is added slightly 
less than the amount of finely ground belladonna 
herb (which has been assayed for its alkaloidal 
content) required to produce a dry extract con- 
taining 1 per cent of alkaloids. The solvent is re- 
moved under reduced pressure at a temperature 
not exceeding 60°. The residue is dried in a cur- 
rent of air at 80°, powdered, the remainder of the 
belladonna herb added, and the whole is passed 
through a No. 22 sieve and mixed. 

Uses. — There is no difference in the thera- 
peutic effects of pilular and powdered belladonna 
extracts. The former may be used in the prepara- 
tion of pills or ointments, the latter in powders, 
capsules or tablets. For conditions in which these 
extracts are useful, see under Atropine. 

The usual dose is 15 mg. (approximately K 
grain), with a range of 10 to 40 mg. (approxi- 
mately % to % grain). 

Storage. — Preserve "in tight containers, pref- 
erably at a temperature not above 30°." N.F. 

Off. Prep. — Belladonna Ointment; Aloin, 
Belladonna, Cascara and Podophyllum Pills, N.F. 

BELLADONNA LEAF FLUID- 
EXTRACT. N.F. 

Fluidextractum Belladonna: Folii 

Belladonna Leaf Fluidextract yields, from each 
100 ml., not less than 270 mg. and not more than 
330 mg. of the alkaloids of belladonna leaf." N.F. 

Liquid Extract of Belladonna Leaf. Extractum Bella- 
donna: Folii Liquidum; Extractum Belladonnas Fluidum. 
It. Estratto fluido di belladonna. 

Prepare the fluidextract from belladonna leaf, 
in moderately coarse powder, either by Process A, 
as modified for assayed fluidextracts, or by Proc- 
ess E (see under Fluidextracts). By Process A 
use a menstruum of 3 volumes of alcohol and 1 
volume of water; macerate the drug during 48 



144 Belladonna Leaf Fluidextract 



Part I 



hours, and percolate at a moderate rate. By Proc- 
esa E use a menstruum of 2 volumes of alcohol 
and 1 volume of water; macerate 1000 Gm. of 
the drug with 400 ml. of menstruum, allow to 
stand 1 hour, pack into a cylindrical percolator or 
a series of percolators having a length about 30 
times the diameter, saturate the drug with men- 
struum under 6 to 15 pounds air pressure and 
macerate during 48 hours, then percolate under 
pressure at a rate of about 1.5 ml. per minute 
until 950 ml. have been collected. In either case, 
adjust the liquid to contain 300 mg. of belladonna 
leaf alkaloids in 100 ml. and 60 per cent, by vol- 
ume, of C2H5OH. X.F. 

Alcohol Content. — From 57 to 63 per cent, 
by volume, of C2H5OH. X.F. 

This preparation is, fortunately, little used in 
the United States. Its potency is relatively great 
and. since only very small volumes would be used 
in the usual prescription mixture, a potentially 
large variation in dosage may arise unless extra 
care is taken to insure accuracy of the volume 
measured. The tincture lends itself to greater 
accuracy, and precision, of measurement. 

The official usual dose of the X.F. preparation 
is 0.06 ml. (approximately 1 minim). 

Storage. — Preserve "in tight, light-resistant 
containers and avoid exposure to direct sunlight 
or excessive heat." X.F. 

BELLADONNA OINTMENT. N.F. 

Unguentum Belladonnas 

''Belladonna Ointment yields not less than 0.110 
per cent and not more than 0.140 per cent of the 
alkaloids of belladonna leaf.*' X.F. 

Pomatum cum Extracto Belladonnas; Pomatum Bella- 
donna;. Fr. Pommade belladonee. Ger. Tollkirschen- 
salbe. It. Unguento di belladonna; Pomato di belladonna. 
Sp. Pomade de belladona; Ungilcnio de Beiladona. 

Triturate 100 Gm. of pilular belladonna extract 
with 50 ml. of diluted alcohol until a smooth mix- 
ture is obtained, then incorporate it with 850 Gm. 
of yellow ointment. X.F. 

Belladonna ointment is a convenient form for 
the external application of belladonna. The most 
important use of the ointment is as a local appli- 
cation in hemorrhoids. Formerly it was used to 
check secretion of breast milk but at present the 
estrogens_have replaced belladonna for this 
purpose. v. 

Storage. — Preserve "in tight containers and 
avoid prolonged exposure to temperatures above 
30°." X.F. 

BELLADONNA TINCTURE. 
U.S.P. (B.P.. I.P.i 

Belladonna Leaf Tincture, Tinctura Belladonnae 

"Belladonna Tincture yields, from each 100 ml., 
not less than 2 7 mg. and not more than 33 mg. 
of the alkaloids of belladonna leaf." U.S.P. The 
B.P. requires 0.03 per cent w v of the alkaloids 
of belladonna herb (leaf), calculated as hyos- 
cyamine (limits. 0.028 to 0.032). The corre- 
sponding LP. limits are 0.02 7 and 0.030 per cent, 
respectively. 

B.P. Tincture of Belladonna. Tincture of Belladonna 
Leaves. Tinctura Belladonnae Foliorum. Fr. Teinture de 
Belladone. Ger. Tollkirschentinktur. It. Tintura di bella- 
* donna. Sp. Tintura de belladona. 



Prepare the tincture, by Process P, as modified 
for assayed tinctures (see under Tinctures), from 
100 Gm. of belladonna leaf, in moderately coarse 
powder, using a menstruum of 3 volumes of alco- 
hol and 1 volume of water. Adjust the volume 
of the product so as to contain 30 mg. of bella- 
donna leaf alkaloids in 100 ml. of tincture. U.S.P. 

The B.P. prepares the tincture from 100 Gm. of 
belladonna herb (leaf; by percolation with 70 per 
cent alcohol to produce 1000 ml. of percolate 
which is diluted, if necessary, to a preparation of 
the required strength. 

Alcohol Content. — From 65 to 70 per cent, 
by volume, of C2H5OH. U.S.P. 

The usual dose is 0.6 ml. (approximately 10 
minims) three times a day, with a range of 0.3 
to 2.4 ml. The maximum single dose is 2.4 ml. and 
not more than 10 ml. should be given in 24 hours. 

Storage. — Preserve "in tight, light-resistant 
containers, and avoid exposure to direct sunlight 
and to excessive heat." U.S.P. 

BELLADONNA ROOT. X.F, B.P, IP. 

Deadly Nightshade Root, Belladonnae Radix 

"Belladonna Root is the dried root of Atropa 
Belladonna Linne (Fam. Solanacece). Belladonna 
Root yields not less than 0.45 per cent of the 
alkaloids of Belladonna Root." X.F. 

The B.P. and LP. recognize the dried root, or 
or root and rootstock of Atropa belladonna L.. or 
of Atropa acuminata Royle ex Lindley or of a 
mixture of both species; not less than 0.40 per 
cent of alkaloids, calculated as hyoscyamine. is 
required. 

Fr. Racine de belladone. Ger. Tollkirschenwurzel; Bella- 
donnawurzel ; Tollwurz. It. Radice di belladonna. Sp. Raiz 
de belladona. 

Atropa Belladonna is an herbaceous perennial, 
with a fleshy root system, from which rise sev- 
eral erect, round, purplish, branching stems, to 
the height of about three feet. The leaves, which 
are attached by short footstalks to the stem, are 
alternate, broadly ovate to ovate, pointed, entire, 
of a dusky green on their upper surface, and paler 
beneath. The flowers are large, tubular-bell- 
shaped, axillary, pendant, of a brownish-purple 
color, with solitary peduncles. The fruit is a sub- 
globular berry with a longitudinal furrow, at first 
green, afterward red, ultimately deep purple to 
black and containing, in two loculi, numerous 
seeds and a sweetish violet-colored juice. The 
5-cleft calyx adheres to the base of the fruit. 

The plant is a native of central and southern 
Europe, where it grows in shady places, along 
walls, and amid rubbish, flowering in June and 
July, and ripening its fruit in September. It grows 
vigorously under cultivation in England. France 
and the United States. For a number of years 
there has been very great interest in the cultiva- 
tion of belladonna in the United States. This in- 
terest has been intensified in recent years owing 
to the greatly reduced imports from abroad, as 
the result of the World Wars, and considerable 
quantities are now produced in this country. 
Plants cultivated in California are very rich in 
active constituents. The yield per acre of stems 
and leaves is somewhat less than one ton. The ex- 



Part I 



Belladonna Root 



145 



periments in California seemed to show that the 
alkaloidal content of belladonna stems may equal 
that of the leaves, ranging from 0.51 to 0.82 per 
cent of total alkaloids. Belladonna leaves grown 
in the shade are uniformly larger, though some- 
what thinner. It is quite likely that the percent- 
age of alkaloids can be increased through selection. 

All parts of the plant are active. The leaves 
and roots, including branches (which are prob- 
ably not less effective when young), are recog- 
nized in the official compendia of the United 
States and Great Britain. The leaves should be 
collected in June or July, when the plant is in 
flower, the roots in the autumn or early in the 
spring, and from plants three to four years old. 
Leaves which have been kept long should not be 
used, as they undergo change through absorption 
of atmospheric moisture, emitting ammonia, and 
probably losing a portion of their active alkaloids. 
Todd (Pharm. J., 1930, 124, 94) has shown that 
loss of alkaloid in the leaves does not take place 
to any extent during careful drying, but if the 
drying process is unduly prolonged, up to one- 
fifth of the total alkaloid may disappear. Enzymes 
appear to be the causative agents in this loss. 
E. Kopp {Pharm. Zentr., 1931, 72, 113) found 
that wild and cultivated belladonna plants had 
the same alkaloidal content when dried in the sun 
as when dried in the shade. Specimens which con- 
tain much stem or are musty should always be 
rejected, as weak in active principle. 

Both herb and root drugs are obtained for the 
most part from plants cultivated in the United 
States, central Europe and England. A total of 
125,394 pounds of belladonna was imported into 
the U. S. A. during 1940 and only 12,387 pounds 
in 1952. During and since World War II most of 
the belladonna leaf and root drugs used in this 
country have been obtained from plants culti- 
vated in the U. S. A. and some of the American- 
grown Belladonna is exported to Europe. 

Atropa lutes cens Jacquem. more properly 
Atropa acuminata Royle, or Indian Belladonna, 
is not generally recognized as a good species by 
botanists (see Index Kewensis, also Hooker's 
Flora of British India, 4, 241). It grows in the 
Himalaya Mountains from Kashmir to Simla. 

Two names have been given the plant yielding 
Indian belladonna, the earlier, Atropa acuminata 
Royle, having been applied to it by Royle in his 
"Illustrations of the Botany of the Himalaya" 
1839, 279. No description accompanied it and 
hence Royle's name is a nomen nudum. However, 
Lindley, in /. Hort. Soc. Lond. (1846), validated 
Royle's name by giving a brief description of 
A. acuminata plants raised in the Society's garden 
in 1845 from seeds collected at Kumaun, India, 
in 1844. 

The name Atropa lutescens Jacquem. appeared 
in manuscripts of Jacquemont and was used by 
Aitchison in his account of the flora of Kurrum 
Valley (/. Linn. Soc, 1881, 18, 82) and some 
other writers. Clarke, in Hooker f., Flora of 
British India, 1885, 4, 241, cited A. lutescens 
Jacquem. Mss. as well as A. acuminata Royle 
as synonyms for A. Belladonna L. The Index 
Kewensis also equates A. lutescens and A. acu- 
minata to A. Belladonna L. Youngken and Hassan 



showed that the A. acuminata is only a variety 
of A. Belladonna and named it Atropa Belladonna 
L. var. acuminata (for details see /. A. Ph. A., 
1948, 37, 450). 

Melville (/. Botany, 1942, 80, 54) investigated 
the botanical source of Indian belladonna and 
found the leaves of Atropa acuminata to be ovate 
elliptic to elliptic lanceolate, acuminate, with a 
gradually tapering base, as contrasted with the 
ovate acute to acuminate leaves of A. Belladonna 
which are stated to have a typically abruptly 
rounded base. He also found the general direc- 
tion of the main lateral nerves made a more acute 
angle with the midrib in A. acuminata than in 
A. Belladonna. Comparing the second and third 
lateral nerves from the base of the leaf, the 
angles were found to be about 30-45° in A. acu- 
minata and 60-75° in A. Belladonna. 

Corfield, Kassner and Collins investigated some 
of the macroscopical characters and the alkaloidal 
content of Indian belladonna (Atropa acuminata). 
They found that on home-grown plants the leaves 
were oblong-elliptical, tapering gradually at both 
the apex and base, and on the flowering tops they 
were more pointed at the apex and less tapering 
at the base, that the flower was yellow to slightly 
greenish yellow, its corolla campanulate to funnel- 
shaped, and the ripe fruit black. The first year 
rootstock was found to be hard and woody, the 
dried root wrinkled longitudinally, tough, and not 
breaking with a short mealy fracture. For home- 
grown plants, the total alkaloid by weight after 
heating on a water-bath for 30 minutes was found 
to be, for leaves and flowering tops, 0.456 per 
cent, and for root, 0.613 per cent (for further 
details see Quart J. P., 1943, 16, 108). Youngken, 
Sr., found branches bearing brownish purple and 
yellow flowers and both black and yellow fruits 
on the same plants of Atropa Belladonna he had 
under cultivation at Jamaica Plain, Mass. 

According to Rowson (Chem. Drug., 1943, 140, 
150), the leaves of Atropa lutescens (A. Bella- 
donna var. acuminata) can be readily distinguished 
microscopically from those of A. Belladonna, 
even in powdered form, by the stomatal index of 
the lower epidermis, it being 21.6 for A. Bella- 
donna, the standard deviation from the mean 
being 1.30, and 17.6 for A. lutescens, the stand- 
ard deviation from mean being 0.71. 

Bulgarian belladonna root, which has received 
considerable publicity during recent years and 
which has been used in the forms of a decoction 
and a wine in the treatment of parkinsonian syn- 
drome, does not differ structurally from ordinary 
belladonna root grown in other countries. Bailey 
(Pharm. J., 1938, 140, 77) did not find any dif- 
ference in chemical constituents. 

Description. — "Unground Belladonna Root is 
cylindrical or tapering, slightly branched, often 
split longitudinally or broken transversely; from 
0.5 to 4 cm. in thickness; weak brown to mod- 
erate yellowish brown externally, light yellowish 
brown to pale yellow internally; somewhat 
wrinkled longitudinally, the soft periderm being 
frequently abraded. The fracture is short and 
mealy, emitting a puff of dust consisting chiefly 
of starch grains. Belladonna Root is nearly odor- 
less when dry but has a characteristic odor when 



146 



Belladonna Root 



Part I 



moistened; it has a sweet, then bitter and acrid 
taste." N.F. For histology see N.F. X. 

"Powdered Belladonna Root is pale brown to 
weak yellow. It contains numerous simple and 
compound starch grains, the single grains up to 
30 n in diameter and showing a distinct, some- 
what eccentric hilum, the polarizing bands in- 
creasing in distinctness in direct ratio to the size 
of the grains; numerous sphenoidal microcrystals 
from 3 to 10 fi in length; a few fragments of 
vessels, tracheids and wood fibers and occasion- 
ally long, thin-walled pericyclic fibers from bella- 
donna stem. Old fibrous roots contain an excess 
of lignified tissue." N.F. 

Standards and Tests. — Belladonna root con- 
tains not over 10 per cent of its stem-bases and 
woody crowns, not more than 2 per cent of for- 
eign organic matter other than stem-bases and 
woody crowns, and not more than 4 per cent of 
acid-insoluble ash. Neither acicular crystals of 
calcium oxalate nor Vessels with diamond-shaped 
bordered pits, indicative of the presence of Phyto- 
lacca root, are seen. N.F. 

Assay. — A sample of 10 Gm. of belladonna 
root is assayed in the same manner as the leaf is 
assayed. N.F. The B.P. and I. P. assays are the 
same as these pharmacopeias respectively specify 
for belladonna herb (leaf). 

Constituents. — Belladonna contains members 
of the group of solanaceous alkaloids. The latter 
term, which may be applied to all alkaloids from 
solanaceous plants, is generally limited to the fol- 
lowing: Atropine and hyoscyamine (C17H23NO3), 
apoatr opine and belladonnine (C17H21NO2), nor- 
hyoscyamine and nor-atropine (C16H21NO3), 
scopolamine or hyoscine (C17H21NO4), tropa- 
cocaine (C15H19NO2), meteloidine (C13H21NO4), 
and some recently discovered minor alkaloids. 
Members of the group are esters of tropic, atropic, 
benzoic, tiglic or other acid with a basic alcohol 
tropine, nor-tropine, atropine, teloidine or sco- 
pine (Henry, Plant Alkaloids, 1949). 

The chief alkaloid of belladonna is hyoscyamine 
with, possibly, some atropine being present. It is 
questionable whether the optically inactive atro- 
pine exists as such, or is produced by racemiza- 
tion of the naturally occurring levorotatory- 
hyoscyamine in the process of extraction (see 
Gorio and Coty, Bull. sc. Pharmacol., 1921, 28, 
545). 

For a description of hyoscyamine and atropine 
see under Atropine. Apoatropine is the anhydride 
of atropine and is prepared by the action of 
dehydrating agents upon atropine or hyoscyamine. 
Hesse reported having isolated this alkaloid, under 
the name atropamine, from belladonna root. Bella- 
donnine, obtained naturally from henbane berries, 
is an isomeride of apoatropine from which latter 
it may be prepared by heating. Nor-hyoscyamine 
is the demethylated derivative of hyoscyamine. 
and has been found naturally in certain plants of 
the Solanaceae. Nor-atropine, the demethylated 
derivative of atropine, is obtained by racemiza- 
tion of nor-hyoscyamine. For a discussion of the 
other alkaloids mentioned above, see elsewhere 
in this work. 

Adulterants. — The usual adulterants of bella- 
donna leaves are the leaves of Phytolacca and 



Ailanthus and the leaves and tops of Solanum 
nigrum and Scopola carniolica. Phytolacca leaves 
may be detected by the presence of numerous 
raphides as well as crystal sand. Scopola leaves 
and tops show characteristic barrel-shaped reticu- 
late tracheae as well as short calyx tubes, each 
having a contained pyxis. Solanum nigrum or 
black nightshade has ovate, wavy-toothed leaves 
and a white rotate corolla. For distinction between 
belladonna and scopola leaves see article by 
Kraemer (Proc. A. Ph. A., 1908, p. 819). Guerin 
and Guillaume describe the anatomical difference 
in the leaves of belladonna, Phytolacca and 
ailanthus (Bull. sc. Pharmacol., 1908, p. 213). 

Belladonna root is not infrequently of inferior 
quality because of the presence of large quanti- 
ties of the stem-bases of the plant. The root is 
sometimes adulterated with Phytolacca or sco- 
pola. Rusby reported the presence of 25 per cent 
of some inert root, apparently wild althea, or a 
relative of that plant. Youngken reported the 
main adulterants of belladonna root as roots of 
Phytolacca decandra, unpeeled roots of Althaa 
officinalis and rhizomes of Scopola carniolica. 
Phytolacca roots possess a tough fibrous fracture 
and exhibit in transverse sections series of con- 
centric circles of open collateral fibrovascular 
bundles; the diagnostic tracheas have diamond- 
shaped bordered pores; as in the case of the 
leaves, raphides and crystal sand are present. 
Althea roots show numerous mucilage sacs, 
sclerenchyma fibers, ellipsoidal starch grains and 
a few rosettes of calcium oxalate. Scopola rhi- 
zomes possess characteristic reticulate tracheae. 

Scopola rhizome has been largely used by manu- 
facturers of belladonna plasters in the place of 
belladonna root. 

Uses. — All parts of the belladonna plant are 
poisonous. It is not uncommon in countries where 
it grows wild for children to pick and eat the 
berries, allured by their fine color and sweet taste. 
The symptoms of belladonna poisoning are pre- 
cisely the same as those of atropine poisoning. 

The conclusion that the active principle of 
belladonna is hyoscyamine, rather than atropine, 
harmonizes with clinical experience which has 
shown that, although qualitatively indistinguish- 
able in its action from atropine, belladonna is 
often efficacious in doses considerably smaller than 
might be expected from its content of alkaloid if 
the latter were atropine (see also Hyoscyamine 
Hydrobromide) . For description of the physio- 
logical and therapeutic properties of belladonna, 
see under Atropine. An important use of bella- 
donna alkaloids has been in the treatment of 
Parkinson's disease (see monograph on Skeletal 
Antispasmodic Compounds, in Part II). 

In the past belladonna root preparations were 
employed topically as in the following instances; 
today they have little more than historic interest. 
Rubbed upon the areola of the breast, belladonna 
has been believed to arrest the secretion of milk 
and was frequently employed in mastitis; its 
utility is questionable. Spasmodic stricture of the 
urethra, anal fissures and painful uterine affections 
have been relieved through local use of the ex- 
tract, either smeared upon bougies or adminis- 
tered by injection or by suppositories. It was 



Part I 



Bentonite 



147 



claimed also to be useful in paraphimosis. The 
inhalation of fumes from burning belladonna 
leaves has been employed to relieve the asthmatic 
paroxysm. For this purpose, 8 Gm. (approxi- 
mately 2 drachms) of the leaves was smoked in 
the form of a cigarette or in a pipe, or the 
coarsely broken leaves, mixed with a little potas- 
sium nitrate, ignited to smolder and emit dense 
fumes to be deeply inhaled. © 

Dose. — The range of dose is 30 to 120 mg. 
(approximately Yi to 2 grains). 

Storage. — Preserve "against attack by in- 
sects." N.F. 

BELLADONNA ROOT FLUID- 
EXTRACT. N.F. (B.P.) 

Fluidextractum Belladonnas Radicis 

"Belladonna Root Fluidextract yields, from 
each 100 ml., not less than 405 mg. and not more 
than 495 mg. of the alkaloids of belladonna root." 
N.F. Liquid Extract of Belladonna of the B.P. 
contains 0.75 per cent w/v of the alkaloids of 
belladonna root calculated as hyoscyamine (limits 
0.70 to 0.80). 

B.P. Liquid Extract of Belladonna; Extractum Bella- 
donnas Liquidum. 

Prepare the fluidextract from belladonna root, 
in coarse powder, by Process A, as modified for 
assayed fluidextracts (see under Fluidextracts) , 
using a menstruum of 4 volumes of alcohol and 
1 volume of water. Macerate the drug during 48 
hours, and percolate at a moderate rate. Adjust 
the liquid to contain 0.45 Gm. of belladonna root 
alkaloids in 100 ml. and 69 per cent, by volume, 
of C2H5OH. N.F. 

Under the name of Liquid Extract of Bella- 
donna, the B.P. recognizes a product of consider- 
ably higher potency than the corresponding prep- 
aration of the N.F. The B.P. liquid extract of 
belladonna root is prepared by percolating 1000 
Gm. of moderately coarse belladonna root with 
80 per cent alcohol. A 400-ml. portion of the 
percolate is reserved; the remainder is evaporated 
to a soft extract under reduced pressure, and the 
residue dissolved in the reserved portion. This 
liquid is assayed for alkaloidal content, adjusted 
to the proper strength, and, after standing at least 
12 hours, filtered. 

Alcohol Content. — From 66 to 71 per cent, 
by volume, of C2H5OH. N.F. 

Belladonna root fluidextract, having a reddish- 
brown color, is markedly different in appearance 
from belladonna leaf fluidextract, which is a deep 
green; the N.F. fluidextract from the root also 
contains half again as much alkaloid (0.45 per 
cent w/v) as the corresponding N.F. preparation 
from the leaf (0.3 per cent w/v). Belladonna root 
fluidextract, even as the preparation from the 
leaf, is little used internally. When called for on 
a prescription special care must be observed to 
measure accurately the volume required; because 
this volume is small, as a rule, it is susceptible to 
relatively large variation. The fluidextract is em- 
ployed externally, for its supposed local anodyne 
effect, in various liniment formulations. The 
N.F. IX recognized Belladonna Liniment prepared 



by dissolving 50 Gm. of camphor in sufficient 
belladonna root fluidextract to make 1000 ml. 

The official usual dose of the N.F. preparation 
is 0.05 ml. (approximately Ya minim) ; the B.P. 
formerly gave as the dose for its stronger prep- 
aration 0.015 to 0.06 ml. (approximately Y to 1 
minim) but the B.P. 1953 makes no mention of 
a dose. 

Storage. — Preserve "in tight, light-resistant 
containers and avoid exposure to direct sunlight 
or to excessive heat." N.F. 



BELLADONNA PLASTER. 

Emplastrum Belladonnas 



N.F. 



"Belladonna Plaster is a mixture of adhesive 
plaster mass and an extract prepared from bella- 
donna root, spread evenly upon fine cotton cloth 
or other suitable backing material. The plaster 
mass yields not less than 0.25 per cent and not 
more than 0.30 per cent of the alkaloids of bella- 
donna root. Each 100 square centimeters of the 
spread plaster contains at least 2.5 Gm. of the 
belladonna plaster mass." N.F. 

Fr. Emplatre d'extrait de belladone. Get. Tollkirschen- 
pflaster. Sp. Emplasto de belladona. 

No method for preparing this plaster is given 
by the N.F. ; for information concerning the 
nature of the adhesive plaster mass which is used 
in this preparation see under Plasters and Ad- 
hesive Plaster. 

Uses. — Although belladonna plaster is widely 
used it is essentially an irrational preparation. 
Sufficient of the active principle may be absorbed 
through the skin to produce constitutional symp- 
toms, but this is manifestly an uncertain and un- 
satisfactory mode of obtaining the general effects 
of belladonna and is never employed for this pur- 
pose. The plaster is used purely as a local anodyne 
in lumbago and other myalgias, but belladonna is 
not an analgesic. Such benefit as has followed the 
employment of belladonna plaster is probably 
attributable more to the mechanical action of the 
plaster than to the therapeutic effect of the bella- 
donna. A popular type of belladonna plaster is one 
in which capsicum is also present. 

Storage. — Preserve "in well-closed containers 
at a temperature which does not exceed 30°. 
Protect it from direct sunlight." N.F. 

BENTONITE. U.S.P., B.P. 

[Bentonitum] 

"Bentonite is a native, colloidal, hydrated alu- 
minum silicate." U.S.P. 

Wilkinite; Soap Clay; Mineral Soap. Sp. Bentonita. 

Bentonite, so named because of its discovery 
in the Fort Benton formation of the Upper 
Cretaceous in Wyoming, was first described by 
Knight in 1897, though it is said to have been 
used at the posts of the Hudson Bay Company 
as a detergent in the washing of woolen materials. 
It is a clay mineral of the class of hydrous alumi- 
num silicates but its composition is quite variable, 
depending on the locality where it is mined. The 
United States Geological Survey defined bentonite 
as "a transported, stratified clay, formed by the 



148 



Bentonite 



Part I 



alteration of volcanic ash, shortly after deposi- 
tion." Of the many available varieties of benton- 
ite, that produced in the Black Hills region of 
Wyoming and South Dakota is reported to be 
of the highest quality; it is variously known as 
northern bentonite, "true" bentonite, and sodium 
bentonite, the last name referring to its contain- 
ing somewhat more sodium than other bentonites 
(though the content of NasO averages only about 
2.5 per cent). The chief mineral constituent of 
this variety is the mineral montmorillonite, hav- 
ing the approximate formula H20.(Al203.Fe2C»3.- 
3MgO).4Si02.nH20, and comprising about 90 per 
cent of the bentonite. The remaining 10 per cent 
consists of a feldspar, gypsum, the clay mineral 
beidellite, calcium carbonate, remnants of altered 
volcanic glass, some crystals of quartz, and a few 
fragments of mica and of a manganese carbonate. 
A relatively small, and variable, proportion of 
the cations of bentonites are exchangeable by 
certain other ions and it is possible to modify 
bentonites by replacing the exchangeable cations 
with others. These exchangeable cations have a 
great deal to do with determining certain physi- 
cal properties of bentonites, notably their hydra- 
tion. A predominance of sodium in the exchange- 
able cation fraction imparts a high degree of 
hydration, while predominance of calcium results 
in lowered degree of hydration. Barr and Guth 
(J. A. Ph. A., 1951, 40, 9) prepared five different 
cation-saturated (sodium, potassium, calcium, 
magnesium, and hydrogen) bentonites from the 
same sample of a natural bentonite by appro- 
priate cation-exchange reactions (see further ref- 
erence to a practical application under Uses). 
Bentonite is chemically similar to kaolin and china 
clay, but it differs physically from these in the 
fineness of its particles, which gives it a greater 
total surface area that is at least partly responsible 
for its pronounced adsorptive capacity. 

Bentonite is insoluble in water but when mixed 
with eight to fourteen parts of the latter it swells 
to produce a slippery paste resembling petroleum 
jelly. The consistency of the gel may be regu- 
lated by varying the amount of water added. Sus- 
pensions containing smaller amounts of bentonite 
are quite permanent, particularly if a fine-particle 
variety of the clay is used. In aqueous suspen- 
sions, the individual particles of bentonite are 
negatively charged, this resulting in a strong at- 
traction for positively charged particles and being 
responsible for the ability of bentonite to clarify 
such liquids as contain positively charged par- 
ticles of suspended matter. 

La Rocca and Burlage (/. A. Ph. A., 1945, 34, 
302) demonstrated that the pH of the medium 
in which bentonite is dispersed has a marked 
effect on the stability of the suspension; above 
about pH 7 the suspensions are considerably more 
stable than below. They also confirmed an earlier 
finding that bentonite, after washing with acid, 
loses its suspending properties because of neu- 
tralization of hydroxyl ions on the surface of the 
bentonite. These hydroxyl ions appear to be essen- 
tial for the formation of the large lattice-like 
structure characteristic of bentonite magmas. For 
other data on bentonite see Ewing et al. (J. A. 
"Ph. A., 1945, 34, 129). 



Description. — "Bentonite occurs as a very 
fine, odorless, pale buff or cream-colored powder, 
free from grit, and has a slightly earthy taste. Ben- 
tonite is insoluble in water, but swells to approxi- 
mately twelve times its volume when added to 
water. It is insoluble and does not swell in 
organic solvents." U.S.P. 

Standards and Tests. — Gel formation. — A 
mixture of 6 Gm. of bentonite and 300 mg. of 
magnesium oxide is added, in divided portions, 
to 200 ml. of water in a 500-ml. glass-stoppered 
cylinder, and agitated thoroughly for 1 hour. A 
100-ml. portion of the mixture is transferred to 
a 100-ml. cylinder, and allowed to remain undis- 
turbed for 24 hours: not more than 2 ml. of 
supernatant liquid appears on the surface. Swell- 
ing power. — A 2-Gm. portion of bentonite is 
added, in divided portions, to 100 ml. of water in 
a glass-stoppered cylinder, allowing each portion 
to settle before adding the next. The mass at the 
bottom of the container gradually swells until it 
occupies an apparent volume of not less than 
24 ml. Fineness of powder. — A suspension of 2 
Gm. of bentonite in enough water to make 100 ml. 
leaves no grit which can be felt with the fingers 
when poured through a No. 200 standard mesh 
sieve, the latter being thoroughly washed with 
water. Loss on drying. — Not less than 5 per cent 
and not more than 8 per cent, when dried at 105° 
for 2 hours. pH. — The pH of a 2 per cent aqueous 
suspension is between 9 and 10. U.S.P. 

Uses. — Bentonite is used for many industrial, 
pharmaceutical, and cosmetic purposes (see re- 
view by Goodman, Arch. Dermat. Syph., 1944, 
49, 264). The better grades are excellent for 
stabilizing many varieties of industrial emulsions 
and other dispersions, such as of latex, various 
oils and waxes, asphalt, etc. It exerts detergent 
effects, being used in soaps, dentifrices, shaving 
creams, and cleaners. Turbid waters and many 
other liquids can be clarified with bentonite, and 
it has marked adsorptive powers for dyes and 
other coloring matter. 

Bentonite is utilized in the preparation of a 
number of pharmaceutical preparations for ex- 
ternal use. Griffon (/. pharm. chim., 1938, 27, 
159) prepared bentonite gels of yellow mercuric 
oxide, mercury, zinc oxide, calomel, sulfur, coal 
tar, etc., simulating the pomades of the French 
Codex but differing from these in not having a 
fatty base. Bentonite has been used as a facial 
pack for cosmetic purposes, and as an adherent 
dressing or an adsorbent powder in dermatology. 
Fantus and Dyniewicz (/. A. Ph. A., 1938, 27, 
878) were able to reduce the rapid sedimentation 
rate of calamine lotion by incorporating ben- 
tonite in the formula. They incorporated bentonite 
also in other dermatological formulas (ibid., 1939, 
28, 548). Hubbard and Freeman (/. A. Ph. A., 
Prac. Ed., 1941, 2, 78) employed a 6 per cent 
stock suspension of bentonite in effecting emulsi- 
fication of troublesome olive oil and lime water 
mixtures, and also in producing improved dis- 
persions of such substances as bismuth subnitrate, 
zinc oxide, sulfur, camphor, etc. Both oil-in-water 
and water-in-oil emulsions were prepared. When 
using bentonite it is essential that it be added to 
water and thoroughly agitated, preferably with 



Part I 



Benzaldehyde 149 



an electric mixer, to permit maximum hydration; 
water should not be added to bentonite. 

Kulchar (Arch. Dermat. Syph., 1941, 44, 43) 
found a 15 per cent suspension of bentonite in 
water to be a satisfactory base, particularly for 
formulations to be used in the treatment of 
dermatitis and pruritus of the anogenital area. 
The bentonite base dries to a film which keeps 
the medication in situ. Salicylic acid, ichthammol, 
ammoniated mercury, resorcinol, sulfur, Naf talan, 
coal tar, Peru balsam, and juniper tar were in- 
corporated in the base. 

Pillsbury, Sulzberger and Livingood (Manual 
of Dermatology, 1942) indicated the multiple 
utility of a powder containing 50 Gm. of zinc 
oxide, 50 Gm. of talc, and 10 Gm. of bentonite 
for preparing a lotion with water, for use as a 
simple dusting powder in which antipruritic agents 
may be incorporated, and for preparing an oint- 
ment by addition of petrolatum to the powder. 

Hopkins (/. Invest. Dermat., 1946, 7, 7) 
treated over 500 cases of fungus skin disease and 
allied conditions using a bentonite gel base (20 
Gm. of bentonite, 15 Gm. of talc, 55 ml. of water, 
5 ml. each of liquid petrolatum and glycerin, and 
5 Gm. of white petrolatum) for various water- 
soluble drugs and also for fatty acids, salicylic 
acid, and other medicaments which may be dis- 
solved in propylene glycol, alcohol, or other sol- 
vent, prior to incorporation with the base. Sulfur, 
ammoniated mercury, zinc oxide, and other in- 
soluble powders were readily incorporated. Thin 
layers only of base are to be applied, as harshly 
acting granules may remain if thick layers are 
used on intertriginous areas or wounds. 

Hollander and McClenahan (ibid., 1948, 11, 
127) devised emulsified ointment bases contain- 
ing petrolatum and bentonite; their formulations 
contained from 10 to 32 per cent of oil phase 
and from 13 to 17 per cent of bentonite. Formulae 
containing higher proportions of oil had greater 
emollient properties and tended to dry less 
readily. These investigators emphasized the non- 
irritating character of the components and the 
rare appearance of allergic skin reactions follow- 
ing use of such ointment bases. The bases were 
especially useful in treating diseases of the lower 
extremities, the bentonite component absorbing 
moisture and removing obnoxious debris from the 
skin. 

Barr and Guth (/. A. Ph. A., 1951, 40, 13), 
taking advantage of the ability of bentonite to 
exchange a portion of its cations, prepared five 
different bentonites, saturated with sodium, po- 
tassium, calcium, magnesium, and hydrogen ions, 
respectively, and used these to prepare bases for 
various ointments. These bases were found to be 
superior to certain official fatty bases as carriers 
for various anti-infective medicaments, judging 
from results of tests utilizing the F.D.A. cup- 
plate method for testing antiseptic ointments. 
They observed that the hydrogen ion-saturated 
bentonite produced ointment bases in which sulfa- 
thiazole, ammoniated mercury, and phenol showed 
greater antibacterial activity than when incor- 
porated in bases containing any of the other 
modified bentonite or the original bentonite from 
which the modified forms were prepared. 



In the form of a gel, bentonite has been used 
as a bulk laxative. Among many other uses it has 
also been employed as a carrier for barium sulfate 
in a preparation administered internally for x-ray 
delineation. 

Storage. — Preserve "in well-closed contain- 
ers." U.S.P. 



BENTONITE MAGMA. 

[Magma Bentoniti] 
Sp. Magma de Bentonita. 



U.S.P. 



Sprinkle 50 Gm. of bentonite, in divided por- 
tions, upon 800 ml. of hot purified water and 
allow the mixture to stand, with occasional stir- 
ring, for 24 hours to permit hydration of the 
bentonite to be completed. Stir until a uniform 
magma is obtained, add enough purified water to 
make 1000 ml., and mix thoroughly. U.S.P. 

This is a convenient form in which to have 
bentonite available for immediate use as a sus- 
pending and emulsifying agent (see under Ben- 
tonite). As hydration of the bentonite is complete 
in the magma, its maximum viscosity has been 
attained and it will therefore be immediately 
effective. 

Storage. — Preserve "in tight containers." 
U.S.P. 

Off. Prep. — Calamine Lotion, U.S.P.; Chalk 
Mixture, N.F. 



BENZALDEHYDE. 

Benzaldehydum 

CeHs.CHO 



N.F. 



"Benzaldehyde contains not less than 98 per 
cent of C 7 H 6 0." N.F. 

Benzoic Aldehyde; Artificial Essential Oil of Almond. 
Oleum Amygdalarum yEthereum Artificiale. Fr. Aldehyde 
benzoique. Ger. Benzaldehyd; Kiinstliches Bittermandelol. 
Sp. Benzaldehido; Bencilal. 

As pointed out elsewhere (see under Bitter 
Almond Oil) benzaldehyde is one of the products 
of the hydrolysis of amygdalin. The commercial 
supply, however, is mostly obtained by synthesis. 
It may be made from toluene by a variety of 
processes. Thus, benzyl chloride, C6H5CH2CI, 
obtained by the chlorination of toluene, yields 
benzaldehyde when treated with water and a mild 
oxidant. If toluene is chlorinated to benzal chlo- 
ride, C6H5CHCI2, this is easily hydrolyzed in the 
presence of either acid or lime to give benzalde- 
hyde. It may also be prepared by the oxidation 
of benzyl alcohol, C6H5CH2OH, as well as by 
other processes. 

Exposed to air, benzaldehyde rapidly oxidizes 
to benzoic acid, the latter frequently contami- 
nating benzaldehyde. 

Description. — "Benzaldehyde is a colorless, 
strongly refractive liquid, having an odor resem- 
bling that of bitter almond oil, and a burning 
aromatic taste. It is affected by light. Benzalde- 
hyde dissolves in about 350 volumes of water, 
and is miscible with alcohol, with ether, and with 
fixed or volatile oils. The specific gravity of 
Benzaldehyde is not less than 1.041 and not more 
than 1.046." N.F. 

Standards and Tests. — Refractive index. — 



150 Benzaldehyde 



Part I 



Not less than 1.5440 and not more than 1.5465, 
at 20°. Hydrocyanic acid. — No greenish blue color 
or blue precipitate (the Prussian blue test) forms 
within 15 minutes after mixing 0.5 ml. of benzal- 
dehyde, 5 ml. of water, 0.5 ml. of sodium hy- 
droxide T.S. and 0.1 ml. of ferrous sulfate T.S., 
warming gently, then acidifying slightly with 
hydrochloric acid. Chlorinated compounds. — A 
roll of copper gauze is heated in a Bunsen burner 
to form a coating of copper oxide; a total of six 
drops of benzaldehyde is ignited on the gauze and 
the latter then heated in the outer edge of a 
Bunsen flame. No green color, due to copper chlo- 
ride vapor, should be seen in the flame. This test 
is commonly known as the Beilstein test for halo- 
gens. Nitrobenzene. — No purplish color is ob- 
tained on treating benzaldehyde with zinc and 
diluted sulfuric acid (whereby nitrobenzene, if 
present, is reduced to aniline) and heating with 
potassium dichromate T.S. A T .F. 

Assay. — Benzaldehyde is assayed in the same 
manner as this constituent is determined quanti- 
tatively in Bitter Almond Oil. Each ml. of 1 N 
sodium hydroxide represents 106.1 mg. of C7H6O. 
N.F. 

Uses. — Benzaldehyde is used chiefly as a 
flavoring agent, having the aroma of bitter al- 
monds without their poisonous qualities. While 
not completely harmless, the toxic powers of 
benzaldehyde are relatively feeble (Viehoever 
and Mack, Am. J. Pharm., 1935, 107, 397). 

The N.F. gives the average dose as 0.03 ml. 
(approximately Yz minim), although it has no 
recognized medicinal action. 

Storage. — Preserve "in w T ell-filled, tight, light- 
resistant containers." N.F. 

Off. Prep. — Compound Benzaldehyde Elixir, 
N.F. 

COMPOUND BENZALDEHYDE 
ELIXIR. N.F. 

[Elixir Benzaldehydi Compositum] 

Dissolve 0.5 ml. of benzaldehyde and 1 Gm. of 
vanillin in 50 ml. of alcohol; add 400 ml. of syrup, 
150 ml. of orange flower water, and enough puri- 
fied water, in portions and shaking the mixture 
after each addition, to make 1000 ml. Filter the 
product, if necessary, until it is clear. N.F. 

Alcohol Content. — From 3 to 5 per cent, by 
volume, of C2H5OH. N.F. 

This elixir is used solely as a pleasant vehicle, 
particularly for administering bromides. 

Storage. — Preserve "in tight containers." N.F. 

Off. Prep. — Three Bromides Elixir, N.F. 

BENZALKONIUM CHLORIDE. U.S.P. 

Alkyldimethyl-benzylammonium Chloride, 
[Benzalkonii Chloridum] 

"Benzalkonium Chloride is a mixture of alkyl- 
dimethyl-benzylammonium chlorides of the gen- 
eral formula, [C6H 5 CH 2 N(CH 3 )2R]C1, in which 
R represents a mixture of the alkyls from CsHu 
to C18H37. It contains, when calculated on the 
anhvdrous basis, not less 97 per cent and not more 
than 103 per cent of [C6H 5 CH2N(CH 3 )2R]C1." 
U.S.P. 



Zephiran Chloride (JWinthrop). Sp. Cloruro de Bengal- 
konio. 

The particular compound which Domagk, in 
1935, called attention to in pointing out the anti- 
septic and detergent properties of certain quater- 
nary ammonium compounds was zephirol, now 
called zephiran chloride, and assigned the title 
benzalkonium chloride by the U.S.P. 

Benzalkonium chloride possesses the structural 
requirements (see also Benzethonium Chloride) 
for a quaternary ammonium compound having 
high germicidal activity, namely, the presence of 
a long alkyl hydrocarbon chain, one short aro- 
matic-substituted alkyl group (benzyl), and two 
lower alkyl groups (methyl). The long alkyl 
hydrocarbon chain is supplied by the fatty acids 
of coconut oil; as the composition of coconut oil 
is reasonably constant a uniform composition of 
the product is assured. 

Description. — "Benzalkonium Chloride occurs 
as a white or yellowish white, amorphous powder, 
or in the form of gelatinous pieces. It has an 
aromatic odor, and a very bitter taste. Its solu- 
tions are alkaline to litmus and foam strongly 
when shaken. Benzalkonium Chloride is very solu- 
ble in w r ater, in alcohol, or in acetone. It is almost 
insoluble in ether, and is slightly soluble in ben- 
zene." U.S.P. 

Standards and Tests. — Identification. — (1) 
A white precipitate, soluble in alcohol, is pro- 
duced on adding diluted nitric acid or mercuric 
chloride T.S. to a 1 in 100 solution of benzal- 
konium chloride. (2) Dissolve 200 mg. of ben- 
kalkonium chloride in 1 ml. of sulfuric acid, add 
100 mg. of sodium nitrate, and heat on a steam 
bath for 5 minutes. Cool, dilute with water to 
10 ml., add 500 mg. of zinc dust, and warm for 
5 minutes on a steam bath. To 2 ml. of the clear 
supernatant liquid add 1 ml. of 1 in 20 sodium 
nitrite solution, cool in ice water, then add 3 ml. 
of a solution of 500 mg. of betanaphthol in 10 ml. 
of ammonia T.S. : an orange-red color is pro- 
duced. (3) A solution of benzalkonium chloride 
in dilute alcohol responds to tests for chloride. 
Water. — Not over 15 per cent, w T hen deter- 
mined by the Karl Fischer method. Residue on 
ignition. — Not over 0.2 per cent. Ammonium 
compounds. — Ammonia is not evolved on heating 
to boiling a mixture of 5 ml. of 1 in 50 solution 
of benzalkonium chloride and 3 ml. of sodium 
hydroxide T.S. U.S.P. 

Assay. — To a solution representing 1 Gm. of 
benzalkonium chloride buffered with sodium ace- 
tate and acetic acid is added an excess of 0.05 M 
potassium ferricyanide which precipitates the 
ferricyanide of benzalkonium; after standing for 
an hour the precipitate is filtered off and the 
excess ferricyanide in an aliquot of the filtrate 
estimated by oxidation of potassium iodide and 
titration with 0.1 N sodium thiosulfate in the 
presence of zinc sulfate. A blank titration is per- 
formed on the potassium ferricyanide solution. 
Each ml. of 0.05 M potassium ferricyanide repre- 
sents 54.0 mg. of alkvldimethyl-benzylammonium 
chlorides. U.S.P. 

Incompatibilities. — Benzalkonium chloride is 
a cationic detergent, i.e., one whose antiseptic 



Part I 



Benzalkonium Chloride 



151 



and detergent properties reside in the cation, and 
as such is incompatible with any anionic detergent, 
such as soap, in which the detergent effect is 
exhibited by the anion. Soap should be completely 
removed from tissue to which benzalkonium chlo- 
ride solution is to be applied. Solutions of local 
anesthetics, of epinephrine and of ephedrine, as 
well as of most other substances with which 
benzalkonium chloride is likely to come in con- 
tact, are compatible with the antiseptic. 

Uses. — Benzalkonium chloride is a powerful 
and rapidly acting germicide for many pathogenic 
nonsporulating bacteria and fungi. Solutions of 
the substance have low surface tension (37.4 
dynes per centimeter for a 1:1000 solution at 
25.3°) and possess detergent, keratolytic and 
emulsifying properties, all of which favor wetting 
and penetration of surfaces to which they are 
applied. In vitro tests demonstrated that Strepto- 
coccus haemolyticus is killed in 10 minutes (but 
not in 5 minutes) by a 1:40,000 solution at 20°, 
and by a 1:95,000 solution at 37°; for Staphylo- 
coccus aureus the corresponding dilutions are 
1:20,000 and 1:35,000; for Eberthella typhosa 
they are 1:20,000 and 1:70,000; and for Esche- 
richia coli, 1:12,000 and 1:40,000 (see Dunn, 
Proc. Soc. Exp. Biol. Med., 1936, 35, 427; ibid., 
1938, 37, 661; Am. J. Surg., 1938, 41, 268; also 
Hoyt et al., Surgery, 1942, 12, 786). In the pres- 
ence of serum the effective concentrations were 
approximately 10 times greater. As with other 
disinfectants it has little sporicidal activity. It is 
less injurious to human leukocytes than are the 
mercurial antiseptics (Herrell and Heilman, Am. 
J. Med. Sc, 1943, 206, 221). 

On the skin, under the usual conditions of use, 
the disinfectant action of benzalkonium chloride 
is not as great as has been generally supposed 
(Price, Arch. Surg., 1950, 61, 23), principally 
because residual soap on the skin inactivates 
the detergent (see under Incompatibilities) . Thor- 
ough rinsing of the area to which benzalkonium 
chloride is to be applied, with water, will ma- 
terially enhance its effectiveness. Price has demon- 
strated that the "tincture" of benzalkonium chlo- 
ride — in which the solvent is composed of 50 per 
cent ethyl alcohol, 10 per cent acetone, and 40 
per cent water — is not only a more effective skin 
disinfectant than an aqueous solution of equal 
concentration, but also is less affected by soap 
than is the aqueous solution. The strongest dis- 
infectant action, according to Price, is produced 
by 1 per cent iodine in 70 per cent alcohol; the 
next strongest is 70 per cent (by weight) alcohol 
by itself; third is the tincture of benzalkonium 
chloride. He suggests that the quaternary com- 
pound may be as effective as iodine if dissolved 
in 70 per cent alcohol. 

Miller et al. {Proc. Soc. Exp. Biol. Med., 1943, 
54, 174) reported that certain cationic antiseptics 
of the type of benzalkonium chloride deposit an 
invisible film on the skin which is difficult to re- 
move. This film may be sterile on the outside but 
underneath it the skin may hold viable bacteria; 
it is readily removed by alcohol or by application 
of an anionic detergent, such as soap. 

Effective concentrations of benzalkonium chlo- 



ride are relatively nonirritating — indeed they are 
said to have an emollient action. A 1:1000 solu- 
tion was given orally to guinea pigs as their only 
source of fluid for months without harmful effect; 
injections intraperitoneally of as much as 6 ml. 
daily of the same solution for several months also 
showed no apparent reaction. Single doses of 1.2 
ml. of a 10 per cent solution p